Convertible plungers and methods for assembling the same in a medical barrel

ABSTRACT

Disclosed are plunger assemblies including various convertible plungers and methods of making the same. Each plunger assembly is configured for disposition within a barrel of a medical container, e.g., a syringe, and displaced within the barrel from an engagement position to a release position. The engagement position is configured to provide a compression seal between a storage sealing section of the plunger and an inner wall of the syringe barrel. In the release position, the compression seal is reduced or eliminated. Also disclosed are methods for making convertible plungers and as assembling them into syringes, e.g., pre-filled syringes.

CROSS-REFERENCE TO RELATED APPLICATIONS

This Application claims priority to U.S. Provisional Application Ser.No. 62/192,192, filed Jul. 14, 2015, 62/269,600, filed Dec. 18, 2015 and62/343,536, filed May 31, 2016, all of which are incorporated byreference herein in their entireties for all purposes.

FIELD OF INVENTION

The invention relates generally to plungers and their use in drugdelivery devices, such as (prefilled, filled before use or empty)syringes, cartridges or auto-injectors. More particularly, the inventionrelates to convertible plungers that provide and maintain containerclosure integrity and gas-tight seal in a storage mode (during the shelflife of, e.g., a prefilled syringe) and then are convertible to adispensing mode. The dispensing mode facilitates relatively low andsmooth/consistent plunger force when dispensing syringe contents.

BACKGROUND

The present disclosure predominantly describes use of convertibleplungers according to the present invention in connection with prefilledsyringes. However, a skilled artisan would readily appreciate that theinvention is not limited to prefilled syringes, but may include otherdrug delivery devices, such as (prefilled, filled before use, or empty)syringes, cartridges and auto-injectors as well as prefilled syringes orother barrels used for diagnostics applications.

Prefilled parenteral containers, such as syringes or cartridges, arecommonly prepared and sold so that the syringe does not need to befilled by the patient or caregiver before use. The syringe, and morespecifically the barrel of the syringe, may be prefilled with a varietyof different injection products, including, for example, salinesolution, a dye for injection, or a pharmaceutically active preparation,among other items.

Prefilled parenteral containers are typically sealed with a rubberplunger, which provides closure integrity over the shelf life of thecontainer's contents. To use the prefilled syringe, the packaging andcap are removed, optionally a hypodermic needle or another deliveryconduit is attached to the distal end of the barrel, the deliveryconduit or syringe is moved to a use position (such as by inserting itinto a patient's tissue or into apparatus to be rinsed with the contentsof the syringe), and the plunger is advanced in the barrel to injectcontents of the barrel to the point of application.

Seals provided by rubber plungers in the barrel typically involve therubber of the plunger being pressed against the barrel. Typically therubber plunger is larger in diameter than the internal diameter of thebarrel. Thus, to displace the rubber plunger when the injection productis to be dispensed from the syringe requires overcoming this pressingforce of the rubber plunger. Moreover, not only does this pressing forceprovided by the rubber seal typically need to be overcome when initiallymoving the plunger, but this force also needs to continue to be overcomeas the rubber plunger is displaced along the barrel during thedispensing of the injection product. The need for relatively elevatedforces to advance the plunger in the syringe may increase the user'sdifficulty in administering the injection product from the syringe. Thisis particularly problematic for auto injection systems where the syringeis placed into the auto injection device and the plunger is advanced bya fixed spring. Accordingly, primary considerations concerning the useof a plunger in a prefilled parenteral container include: (1) containerclosure integrity (“CCI”, defined below) and gas-tightness; and (2)plunger force (defined below) required to dispense syringe contents.

In practice, maintaining CCI/gas-tightness and providing desirableplunger force tend to be competing considerations. In other words,absent other factors, the tighter the fit between the plunger and theinterior surface of the container to maintain adequateCCI/gas-tightness, the greater the force necessary to advance theplunger in use. In the field of medical syringes, it is important toensure that the plunger can move at a substantially constant speed andwith a substantially constant and relatively low force when advanced inthe barrel. In addition, the force necessary to initiate plungermovement and then continue advancement of the plunger should be lowenough to enable comfortable administration by a user and preventjolting or unnecessarily high pressing force that can cause patientdiscomfort.

Plunger force is essentially a function of the coefficients of frictionof each of the contacting surfaces (i.e., the plunger surface andinterior syringe wall surface) and the normal force exerted by theplunger against the interior wall of the syringe. The greater therespective coefficients of friction and the greater the normal force,the more force required to advance the plunger. Accordingly, efforts toimprove plunger force should be directed to reducing friction andlowering normal force between contacting surfaces. However, such effortsare preferably tempered by the need to maintain adequate CCI andgas-tightness, as discussed above.

To reduce friction and thus improve plunger force, lubrication istraditionally applied to the barrel-contacting engagement surface of theplunger, the interior surface of the barrel, or both. Liquid or gel-likeflowable lubricants, such as free silicone oil (e.g.,polydimethylsiloxane or “PDMS”), may provide a desired level oflubrication between the plunger and the barrel to optimize plungerforce. PDMS is, in fact, a standard flowable lubricant used in theindustry. However, for preferred embodiments of the invention, use offlowable lubricant between the plunger and the barrel is not desired.One reason is that a flowable lubricant can mix and interact with thedrug product in a syringe, potentially degrading the drug or otherwiseaffecting its efficacy and/or safety. Degradation is particularly anissue in the case of protein compositions and polypeptide compositions,which occupy a market with tremendous growth potential. Further, suchlubricants may in some cases be problematic if they are injected intothe patient along with the drug product. In addition, flowablelubricants, when used with prefilled syringes, may migrate away from theplunger over time, resulting in spots between the plunger and theinterior surface of the container with little or no lubrication. Thismay cause a phenomenon known as “sticktion,” an industry term for theadhesion between the plunger and the barrel that needs to be overcome tobreak out the plunger and allow it to begin moving. For these reasons,there is an industry need for an “oil free” solution, i.e., a plungerthat is entirely or at least substantially free of flowable lubricantbetween the plunger and the barrel and wherein such flowable lubricantis absent from the drug product stream.

As an alternative (or in addition) to flowable lubricants, plungers maybe made from materials having lubricious properties or includefriction-reducing coatings or film laminates on their exterior surfaces.Examples of such plungers include, for example: the i-COATING by TERUMO,which is disclosed in Canadian Patent No. 1,324,545, incorporated byreference herein in its entirety; W.L. Gore extended ETFE film on arubber plunger; and the CZ plunger by WEST. However, film coatedplungers alone are considered to provide inadequate CCI or gas-barrierproperties. For example, while fluoropolymer films on plungers provideexcellent lubricious properties, they are known to provide poor gasbarriers. Accordingly, a conventional fluropolymer film laminatedplunger alone may not be a viable solution for a prefilled syringe thathouses product which is sensitive to certain gases.

Thus, there is a need for plungers that balance desirable plunger forcein a parenteral container with maintaining adequate CCI and (as the casemay be) gas-tight sealing to prevent drug leakage, protect the drugproduct and attain sufficient product shelf life. In addition, there isa need to provide adequate lubricity to achieve a desired plunger forcewhile preventing adverse effects of flowable lubricant-generatedparticles and interaction with the drug product held by the container.There is a further need to optimize these factors while reducingmanufacturing costs and complexity. The subject invention preferablyaddresses those needs, and others.

SUMMARY OF THE INVENTION

One aspect of this invention is a convertible plunger. The convertibleplunger has an internal portion and a generally cylindrical exteriorsurface that surrounds at least part of the internal portion. Thegenerally cylindrical exterior surface includes a compressible andresilient storage sealing section that is maintained in an expandedstate by outward radial pressure provided by the internal portion. Theinternal portion is comparatively more rigid than the storage sealingsection. The expanded state is reducible to a constricted state by anoperation that is applied to the internal portion of the plunger toreduce or eliminate the outward radial pressure. The storage sealingsection, in the constricted state, has a reduced maximum diameter orcross-sectional width than the storage sealing section in the expandedstate and/or is less resistant to inward radial compression compared tothe storage sealing section in the expanded state. The storage sealingsection is configured to be set in the expanded state throughapplication of a setting force onto the convertible plunger in a distaldirection, optionally when the convertible plunger is disposed in amedical barrel. The operation is application of an actuation force ontothe convertible plunger in the distal direction, optionally when theconvertible plunger is disposed in a medical barrel.

Another aspect of this invention is a pre-filled syringe having aconvertible plunger according to any embodiment disposed therein. Thepre-filled syringe, according to an optional embodiment, includes amedical barrel having an inner wall and an injectable drug product,optionally a liquid composition, disposed in a product containing areaof the medical barrel. The medical barrel has a distal dispensing endfor dispensing the injectable drug product and an open proximal endconfigured for receipt of a convertible plunger.

Optionally in any embodiment of a syringe according to the invention,the convertible plunger provides a break loose force and glide forcebelow 15 N, optionally below 10 N, optionally below 9 N, optionallybelow 8 N, optionally below 7 N, optionally below 6 N, optionallybetween 2.5 N and 5.5 N, entirely without the presence of a flowablelubricant between the inner wall of the medical barrel and theconvertible plunger's barrel-contacting surfaces.

Optionally in any embodiment of a convertible plunger according to theinvention, a plunger head is provided at a distal end of the convertibleplunger. The plunger head includes a liquid sealing section configuredto provide a liquid tight seal and optionally a CCI seal against aninner wall of a medical barrel. The plunger head comprises a firstcomponent. The storage sealing section is mounted to and axially movableabout a second component or integral with the second component. Thefirst component and second component are separate components that areassembled to form the convertible plunger.

Optionally in any embodiment of a pre-filled syringe according to theinvention, the injectable drug product, optionally a liquid composition,disposed in a product containing area of the medical barrel, includes apolypeptide composition or protein composition. In this optionalembodiment, desirable plunger forces are achieved entirely without thepresence of a flowable lubricant between the inner wall of the medicalbarrel and the convertible plunger's barrel-contacting surfaces. Inaddition, flowable lubricant-generated particles are absent from thedrug product.

In an optional aspect, the invention is a method for assembling aconvertible plunger into a medical barrel to form a syringe. Such amethod may include providing a medical barrel, inserting a convertibleplunger through an open proximal end of the barrel, disposing theplunger within the medical barrel proximal to the product containingarea. The method includes applying a setting force onto the convertibleplunger in a distal direction in order to set the storage sealingsection in the expanded state, thereby placing the convertible plungerin the storage mode. A convertible plunger, as may be used in thismethod, may include an internal portion and a generally cylindricalexterior surface that surrounds at least part of the internal portion.The generally cylindrical exterior surface has a compressible andresilient storage sealing section that is maintained in an expandedstate by outward radial pressure provided by the internal portion,thereby rendering the convertible plunger in storage mode. The internalportion is comparatively more rigid than the storage sealing section.The expanded state is reducible to a constricted state by an operationthat is applied to the internal portion of the plunger to reduce oreliminate the outward radial pressure to transition the convertibleplunger from the storage mode to a dispensing mode. The storage sealingsection in the constricted state has a reduced maximum diameter orcross-sectional width than the storage sealing section in the expandedstate and/or is less resistant to inward radial compression compared tothe storage sealing section in the expanded state. Optionally, accordingto this method, the convertible plunger in the storage mode isconfigured to transition to the dispensing mode upon providing anactuation force onto the convertible plunger in a distal direction.Optionally, according to this method, the syringe is pre-filled in amanufacturing filling process with a drug product in the productcontaining area. Optionally, according to this method, flowablelubricant is absent from the product containing area.

Optionally, according to any embodiment of a syringe according to theinvention, the barrel is made from an injection moldable thermoplasticresin, optionally COP or COC.

Optionally, according to any embodiment of a syringe according to theinvention, the barrel has an organo-siloxane coating or layer on theinterior wall of the barrel, optionally wherein the organosiloxanecoating or layer is a pH protective coating, optionally as a top layerof a tri-layer coating set.

Optionally, according to any embodiment of a pre-filled syringeaccording to the invention, the storage sealing section in the expandedstate forms a liquid-tight, CCI and gas-tight interface with theinterior wall of the barrel, optionally wherein the gas-tight interfaceis substantially impermeable to oxygen, nitrogen, water vapor and/orethylene oxide.

Optionally, according to any embodiment of a pre-filled syringeaccording to the invention, the storage sealing section in the expandedstate forms a CCI and gas-tight seal over a product shelf-life of 6months, one year, optionally 18 months, optionally 24 months, optionallythree years.

Optionally, according to any embodiment of a pre-filled syringeaccording to the invention, the plunger provides a differential betweenbreak loose force and glide force of optionally below 20%, optionallybelow 15%, optionally below 12%, optionally below 10%, optionally below8%, optionally between 2.5% and 6% entirely without the presence of aflowable lubricant between the barrel and the plunger'sbarrel-contacting surfaces.

Optionally, according to any embodiment, the convertible plunger issecured to a plunger rod, forming a plunger assembly, wherein theplunger rod is configured to be pressed in a distal direction to actuatethe plunger and dispense drug product.

Optionally, according to any embodiment of a pre-filled syringeaccording to the invention, the drug product is an injectable liquidselected from the group consisting of: a small molecule pharmaceuticaldrug product, a biologic, a vaccine, a peptide-based drug, aprotein-based drug, sterile water or saline solution for injection and adiagnostic medium.

Optionally, according to any embodiment of a pre-filled syringeaccording to the invention, the drug product is selected from groupconsisting of: diagnostic agents (e.g., dyes or contrast agents),vaccines, injections for research purposes (e.g., placebos),chemotherapeutic agents, contrast agents, immunogens, antigens,interferons, polyclonal antibody preparations, monoclonal antibodies,anesthetics, interfering RNAs, gene vectors, insulins, carriers,excipients, diluents and combinations of two or more of the foregoing.

Optionally, according to any embodiment of a pre-filled syringeaccording to the invention, a drug product disposed in the syringe isselected from the group of biopharmaceutical products set forth inBIOPHARMA: Biopharmaceutical Products in the U.S. and EuropeanMarkets-Recent U.S. Approvals, Jul. 13, 2016, pp. 1-20,http://www.biopharma.com/approval.htmI, which is incorporated byreference herein in its entirety for all purposes. It is contemplatedthat at least some of these biopharmaceutical products are susceptibleto one or more negative effects from interaction with particlesgenerated from a flowable lubricant. Such negative effects may include:denaturing of proteins in the composition, agglomeration of proteins inthe composition, degradation of proteins in the composition, triggeringan undesired immune response in a patient who is administered the drugproduct and degrading efficacy of the drug product. In an optionalembodiment of the invention, flowable-lubricant generated particles areabsent from the biopharmaceutical drug product such that the drugproduct is not subject to the one or more of the aforementioned negativeeffects from flowable-lubricant generated particles.

Optionally, according to any embodiment of a syringe according to theinvention, the medical barrel is made from glass.

Optionally, according to any embodiment of a syringe according to theinvention, the convertible plunger includes a liquid sealing sectionthat is located distal to the storage sealing section. The liquidsealing section includes a film coating having a lower coefficient offriction than a substrate to which the film coating is applied. The filmcoating is optionally a fluoropolymer film. The liquid sealing sectionpreferably provides a liquid tight seal against the inner wall of thebarrel.

Optionally, according to any embodiment of a plunger or pre-filledsyringe according to the invention, the storage sealing section includesat least two annular ribs separated by an annular valley therebetween.

Optionally, any embodiment of a pre-filled syringe according to theinvention may be a component of an auto injector.

Optionally, any embodiment of a syringe according to the invention is a0.5 mL syringe. Optionally, any embodiment of a syringe according to theinvention includes a barrel having an inner diameter of from 2.5 mm to4.6 mm. Applicants have successfully reduced to practice a functionalconvertible plunger in a 0.5 mL syringe. It is a notable achievementthat a convertible plunger, with small separate cooperating components,is workable in such small syringe dimensions.

Optionally, for any embodiment of a syringe according to the invention,the storage sealing section is on an outer storage ring disposed aboutthe convertible plunger. The convertible plunger is configured toaxially translate distally relative to the storage ring whentransitioning from storage mode to dispensing mode.

Optionally, for any embodiment of a pre-filled syringe according to theinvention, the injectable drug includes a polypeptide composition orprotein composition that is susceptible to one or more negative effectsfrom interaction with particles generated from a flowable lubricant.Such negative effects may include: denaturing of proteins in thecomposition, agglomeration of proteins in the composition, degradationof proteins in the composition, triggering an undesired immune responsein a patient who is administered the drug product and degrading efficacyof the drug product.

In one aspect, the invention is optionally directed to a method forusing any syringe embodiment disclosed herein for ophthalmicapplications. The syringe for such applications contains 5-50microliters, optionally 10-30 microliters, optionally 10-20 microlitersof ophthalmic drug in the product-containing space. The barrel has aninner diameter of from 2.5 mm to 4.6 mm. The method includes inserting aneedle into a patient's eye tissue wherein the needle provides fluidcommunication from the product-containing area through the dispensingend of the barrel and actuating the convertible plunger to transitionfrom storage mode to dispensing mode. The “inserting” step may precedethe “actuating” step or vice versa. Further, the method includesinjecting the ophthalmic drug into the patient's eye tissue.

In another optional embodiment, the invention is a convertible plungerfor disposition within a barrel of a medical container. The barrel isconfigured for receipt of an injectable product therein and having acentral axis and an interior wall surrounding the axis. The plunger isconfigured to be moved within the barrel along the axis from a storagemode to a dispensing mode. The plunger includes a ring carrier having acompressible and resilient storage ring disposed thereon. The ring isconfigured to displace axially, optionally by sliding, along the ringcarrier from an engagement position to a release position. In theengagement position, the storage ring is disposed about a storageplatform of the ring carrier. In the release position, the storage ringis disposed about a dispensing platform having a narrower maximumcross-sectional width or diameter than the storage platform. The storageplatform is optionally comparatively more rigid than the storage ring.The storage ring includes a storage sealing section configured to applyoutward radial pressure on the interior wall when the storage sealingsection is in the engagement position. The storage sealing section isconfigured in the release position to provide reduced or no outwardradial pressure on the interior wall. The plunger further includes aplunger head mounted at a distal end of the plunger, the plunger headhaving a liquid sealing section configured to contact and provide a sealagainst the interior wall. The plunger head is a separate componentassembled with the ring carrier, directly or indirectly, to form theconvertible plunger.

In another optional embodiment, the invention is a convertible plunger.The plunger includes first and second subassemblies secured to eachother. The first subassembly includes an optionally polymeric andoptionally generally cylindrical connector body having a distal end anda proximal end. The first subassembly further includes a plunger head,which is a separate component that is assembled to the distal end of theconnector body. The plunger head has a liquid sealing section configuredto contact and provide a seal against an interior wall of a medicalbarrel when disposed therein. The second subassembly includes anelongate ring carrier, which is optionally polymeric, having a distalend and a proximal end. The distal end of the ring carrier is secured tothe proximal end of first subassembly. The proximal end of the ringcarrier is configured to be secured to a plunger rod. The ring carriercomprises, from its proximal end, an annular dispensing platform and anannular storage platform distal to the dispensing platform. The annularstorage platform has a larger maximum diameter or cross-sectional widththan the dispensing platform. The second subassembly further includes acompressible and resilient storage ring, which is optionallyelastomeric, disposed about the ring carrier and configured to displaceaxially thereon, optionally to slide axially thereon. The storageplatform is optionally comparatively more rigid than the storage ring.Optionally, the proximal end of the connector body includes a recess oraxial channel, the ring carrier further including an annular insertionplatform distal to the annular storage platform. The annular insertionplatform has a smaller maximum diameter or cross-sectional width thanthe storage platform. The insertion platform is disposed in the recessor axial channel so as to fixedly secure the first subassembly to thesecond subassembly.

Optionally, according to any embodiment of a convertible plungeraccording to the invention, there is a fluoropolymer film wrapped aboutthe liquid sealing section.

Optionally, according to any embodiment of a convertible plungeraccording to the invention, the storage ring includes at least twoannular ribs separated by an annular valley therebetween. Optionally,the storage ring includes exactly three annular ribs with exactly twoannular valleys respectively separating the ribs.

Optionally, according to any embodiment of a convertible plungeraccording to the invention, the storage ring in an uncompressed stateincludes a rib on an inside surface of the storage ring and an opposingrib on the outer surface of the storage sealing section. The opposingribs have peaks that are preferably aligned along the same radial plane.

Optionally, according to any embodiment of a convertible plungeraccording to the invention, the storage ring includes an outer surfacefacing generally radially outward away from the ring carrier. When thestorage ring is in an uncompressed state, the outer surface comprises aproximal end, a distal end and a radial plane of symmetry between theproximal and distal ends, optionally equidistant from the proximal anddistal ends, wherein the outer surface is symmetrical on either side ofthe radial plane of symmetry.

Optionally, according to any embodiment, the convertible plunger may bedisposed in a pre-filled syringe. When the storage ring is disposedabout the storage platform, the storage sealing section is maintained inan expanded state by outward radial pressure provided by the storageplatform to create compression between the storage sealing section andthe inner wall of the barrel. This renders the convertible plunger instorage mode. The expanded state is reducible to a constricted stateupon transitioning the storage ring to being disposed about thedispensing platform whereupon the compression between the storagesealing section and the inner wall of the barrel is reduced oreliminated, thereby rendering the convertible plunger in dispensingmode. Optionally, the entire storage ring is disposed about the storageplatform when the plunger is in storage mode. Optionally, the entirestorage ring is disposed about the dispensing platform when the plungeris in dispensing mode. Optionally, the storage sealing section isconfigured to be set in the expanded state through application of asetting force onto the convertible plunger in a distal direction.Optionally, the convertible plunger in storage mode is configured totransition to dispensing mode upon providing an actuation force onto theconvertible plunger in a distal direction.

In an optional embodiment, the invention is an assembly including aplunger head that has a compressible and resilient material, optionallyan elastomer or thermoplastic elastomer. The plunger head is configuredfor providing a seal, optionally a liquid tight seal when disposed in amedical barrel. The plunger includes a distal product-facing surface, aproximal end and a sidewall therebetween configured for contacting aninner wall of a medical barrel to form the seal when disposed in themedical barrel. The assembly further includes a rigid component or rigidsubassembly, optionally a ring carrier, a central core and/or aconnector body, fixedly secured at a distal end of the rigid componentor rigid subassembly, to the proximal end of the plunger head. Afluoropolymer film piece is wrapped about the plunger head, entirelycovering the product-facing surface and sidewall. The fluoropolymer filmpiece has an edge about its perimeter, wherein the edge is not exposedon the assembly. For example, the edge may be sandwiched between theplunger head and the rigid component or rigid subassembly.

In an optional embodiment, the invention is a method for making afluoropolymer film coated liquid sealing section for a plunger,optionally as a component of a convertible plunger, according to variousprocess steps disclosed herein. Optionally, the plunger head comprisesan elastomer disposed over a polymer support. The plunger head isoptionally made through two-shot injection molding. Optionally, theelastomer of the plunger head comprises a polyolefin based thermoplasticelastomer and the polymer support comprises a polyolefin, optionallypolypropylene, cyclic olefin polymer or cyclic olefin copolymer.

In an optional embodiment, the invention is a method for making anassembly. The method includes providing a plunger head comprising acompressible and resilient material, optionally an elastomer, disposedover a comparatively more rigid polymer support. The plunger headincludes a distal product-facing surface, a proximal end and a sidewalltherebetween configured for contacting an inner wall of a medical barrelto form a seal, optionally a liquid tight seal, when disposed in amedical barrel. Optionally, a fluoropolymer film is wrapped about theplunger head, entirely covering the product-facing surface and sidewall.The method further includes providing a polymeric and optionallygenerally cylindrical connector body having a distal end and a proximalend, the proximal end of the plunger head being assembled to the distalend of the connector body and optionally secured thereto by joining,optionally by welding (e.g., ultrasonic welding), the rigid support ofthe plunger head to the distal end of the connector body. Respectivematerials of the rigid support and connector body are configured to becompatible with each other for ultrasonic welding. The method furtherincludes providing an elongate polymeric ring carrier having a distalend and a proximal end. The distal end of the ring carrier is assembledto the proximal end of the connector body. The ring carrier comprises amaterial having lower gas permeability, optionally lower oxygenpermeability, nitrogen permeability, water vapor permeability and/orethylene oxide permeability, than the connector body. Optionally, aspart of the method, an elastomeric storage ring is disposed about thering carrier. The ring carrier is configured to displace axiallyrelative to the storage ring. However, broadly, this embodiment is notlimited to convertible plungers and the storage ring may be omitted inappropriate cases, e.g., for non-prefilled syringe applications.

Optionally, in any embodiment, the storage ring is an elastomer.

Optionally, in one embodiment, the invention is a method for assemblinga convertible plunger into a pre-filled syringe. The method includesproviding a syringe barrel having a central axis and an interior wallsurrounding the axis, the barrel including a dispensing end, an open topand a product containing area therebetween. The product containing areais pre-filled to a desired amount with an injectable drug product,optionally a liquid composition. A first subassembly is provided andincludes a rigid and generally cylindrical connector body having adistal end and a proximal end. The proximal end has a recess or axialchannel. The first subassembly further includes a plunger head, which isa separate component that is assembled to the distal end of theconnector body. The plunger head has a liquid sealing section configuredto contact and provide a seal against the interior wall of the barrelwhen disposed therein. A second subassembly is provided. The secondsubassembly has a rigid elongate ring carrier having a distal end and aproximal end. The distal end is configured to be secured to the firstsubassembly. The proximal end is configured to be secured to a plungerrod. The ring carrier includes, from its proximal end, an annulardispensing platform, and an annular storage platform distal to thedispensing platform. The annular storage platform has a larger maximumdiameter or cross-sectional width than the dispensing platform. There isan annular insertion platform distal to the annular storage platform,the annular insertion platform having a smaller maximum diameter orcross-sectional width than the storage platform. The second subassemblyfurther includes a compressible and resilient storage ring, which isoptionally elastomeric, disposed about the ring carrier and configuredto displace axially thereon, optionally to slide axially thereon. Thefirst subassembly is loaded into the syringe barrel, with the plungerhead located distally in the barrel with respect to the connector body,the loading step optionally being achieved through a vent tube, vacuumor vacuum assist loading method. The method further includes positioningthe storage ring about the insertion platform and axially aligning thesecond subassembly with the recess or axial channel of the connectorbody, the distal end of the ring carrier facing the recess or axialchannel. After positioning and aligning, the method includes moving thefirst subassembly toward the second subassembly and/or vice versa todispose the second subassembly into the syringe barrel, whereupon theinsertion platform is inserted into the recess or axial channel whilethe storage ring contacts the proximal end of the connector body. As theinsertion platform is further inserted into the storage ring, thestorage ring is pushed off the insertion platform and is disposed aboutthe storage platform, creating a compression seal between the storagering and the interior wall of the barrel and fixedly securing the firstsubassembly to the second subassembly. In this way, convertible plungermay optionally be assembled. Optionally by this method, a pressure zoneis not created between the storage ring and the first subassembly or theplunger head. Optionally, the convertible plunger in storage mode isconfigured to transition to a dispensing mode upon providing anactuation force onto the convertible plunger in a distal direction.

In an optional embodiment, the invention is a convertible plungerassembly configured to be disposed within a syringe barrel and advancedin a dispensing direction to dispense the contents of the syringebarrel. The plunger assembly includes a plunger having an axial cavityand at least two axially spaced generally annular ribs. Each rib has aninner diameter and an outer diameter, joined by an intermediate sleeveportion of reduced outer diameter. The plunger assembly further includesa sliding shaft that is received in the axial cavity and displaceablealong its axis. The sliding shaft includes at least one annularcylindrical ring and at least one reduced diameter portion axiallydisplaced from the ring.

Additional methods for making plunger assemblies and inserting them intoprefilled syringes are disclosed.

BRIEF DESCRIPTION OF THE DRAWINGS

The invention will be described in conjunction with the followingdrawings in which like reference numerals designate like elements andwherein:

FIG. 1 is an axial sectional view of one exemplary syringe constructedin accordance with this invention.

FIG. 1A is an enlarged sectional view of a first alternative embodimentof the inner surface of the syringe of FIG. 1, comprising a tri-layercoating set disposed thereon.

FIG. 1B is an enlarged sectional view of a second alternative embodimentof the inner surface of the syringe of FIG. 1, comprising anorgano-siloxane coating disposed thereon.

FIG. 2A is an enlarged axial sectional view of a portion of aconvertible plunger forming a portion of the syringe shown in FIG. 1,with the plunger being shown in its engagement position in the syringe,wherein its storage sealing section forms a liquid-tight and gas-tightinterface with the interior wall of the syringe and its liquid sealingsection forms a liquid-tight interface and preferably a CCI seal withthe interior wall of the syringe.

FIG. 2B is an enlarged sectional view, similar to FIG. 2A, but showingthe convertible plunger as it is moved from its engagement position to arelease position wherein its storage sealing section no longer forms aliquid-tight and gas-tight interface with the interior wall of thesyringe but its liquid sealing section still forms a liquid-tightinterface and preferably CCI seal with the interior wall of the syringe.

FIG. 2C is an enlarged sectional view similar to FIGS. 2A and 2B butshowing the convertible plunger in its most fully released position.

FIG. 3A is an enlarged, exploded, axial sectional view of the exemplaryembodiment of the convertible plunger of FIG. 1 in the process of beingassembled.

FIG. 3B is an enlarged axial sectional view of the exemplary embodimentof the convertible plunger of FIG. 3A but shown after it has beenassembled.

FIG. 4A is an enlarged axial sectional view of another exemplaryembodiment of a convertible plunger constructed in accordance with thisinvention, and which convertible plunger can be used in any applicationthat the convertible plunger shown in FIG. 1 can be used.

FIG. 4B is a sectional view taken along line 4B-4B of FIG. 4A.

FIG. 5A is an enlarged axial sectional view of still another exemplaryembodiment of a convertible plunger constructed in accordance with thisinvention shown in the process of assembling the plunger.

FIG. 5B is an enlarged axial sectional view, similar to FIG. 5A, butshowing the plunger after it has been assembled, whereupon it can beused in any application that the convertible plunger shown in FIG. 1 canbe used.

FIGS. 6A-6E constitute a series of enlarged isometric views of a portionof the syringe shown in FIG. 1 during the assembly of its convertibleplunger.

FIG. 7 is an axial sectional view of an exemplary plunger constructed inaccordance with this invention, illustrating an optional configurationfor applying film thereto.

FIG. 8 is an exploded axial sectional view of an exemplary plungerconstructed in accordance with this invention, illustrating anotheroptional configuration for applying film thereto.

FIG. 9 is an exploded axial section view of an exemplary plungerconstructed in accordance with this invention, illustrating yet anotheroptional configuration for applying film thereto.

FIG. 10 is a perspective view of an exemplary convertible plungerconstructed in accordance with this invention, illustrating athree-ribbed storage sealing section.

FIG. 11 is a side view of the convertible plunger of FIG. 10.

FIG. 12 is an axial sectional view of the convertible plunger of FIG.10.

FIG. 12A is an axial sectional view of an alternative geometry anddimensions for a plunger head of a liquid sealing section according toan optional embodiment.

FIG. 13 is a schematic illustration of an embodiment of a plungerinsertion apparatus for inserting the plunger of FIG. 10 into a medicalbarrel.

FIG. 14A is a partial schematic illustration of an alternativeembodiment of a plunger insertion apparatus, according to an aspect ofthe invention, for inserting the plunger of FIG. 10 into a medicalbarrel, wherein the storage ring is in a pre-storage sealing mode.

FIG. 14B is the same partial schematic illustration as FIG. 14A, exceptthat the storage ring is set in storage sealing mode.

FIG. 14C is a more complete schematic illustration of FIG. 14A, showingadditional components of the plunger insertion apparatus.

FIG. 15A is a partial schematic illustration of an alternativeembodiment of a plunger insertion apparatus, according to an aspect ofthe invention, for inserting the plunger of FIG. 10 into a medicalbarrel, wherein the storage ring is set in storage sealing mode.

FIG. 15B is a more complete schematic illustration of FIG. 15A, showingadditional components of the plunger insertion apparatus, wherein thestorage ring is in a pre-storage sealing mode.

FIG. 16A is a sectional schematic illustration of a plunger insertionapparatus, according to an aspect of the invention, for an exemplaryembodiment of an insert and sleeve convertible plunger.

FIG. 16B is a partial schematic illustration of the plunger insertionapparatus of FIG. 16A, oriented 90 degrees from the view shown in FIG.16A.

FIG. 17A is a partial cross-sectional view of an alternative plungerinsertion apparatus, according to an aspect of the invention, foranother exemplary embodiment of an insert and sleeve convertibleplunger.

FIG. 17B is a perspective view of the plunger insertion apparatus andplunger of FIG. 17A.

FIG. 18 is a cross-sectional view of an alternative embodiment of aconvertible plunger according to an aspect of the invention with anoptional plunger insertion apparatus assembling the plunger into amedical barrel.

FIG. 19A is a chart detailing the average plunger force profile ofplungers according to an embodiment of the present invention, asdiscussed in Example 1 herein.

FIG. 19B is a chart of the raw data for plunger force of the eighteenplungers that were tested, as discussed in Example 1 herein.

FIG. 20 is a chart of plunger force, discussed also in Example 1, foranother set of similarly configured plungers and syringes as thosetested and described with respect to FIGS. 19A and 19B.

FIG. 21 is an axial sectional view of an alternative convertible plungerembodiment comprising a connector, which at a distal end thereof, issecured to the liquid sealing section and at a proximal end thereof, issecured to the central core.

FIGS. 22A and 22B are schematic drawings illustrating the manner inwhich the convertible ring of FIG. 21 may be assembled.

FIGS. 23A-23C are schematic drawings illustrating the manner in whichthe convertible plunger components of FIG. 21 may be loaded into andassembled within a syringe barrel.

FIG. 24 is an axial sectional view of an alternative convertible plungeridentical to the plunger of FIG. 21, except that the cross-section ofthe storage ring of FIG. 24 is an alternative geometry compared to thatof FIG. 21.

FIG. 24A is an enlarged partial view of the plunger of FIG. 24highlighting the alternative geometry of the cross-section of thestorage ring.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

The present invention will now be described more fully with reference tothe accompanying drawings, in which several embodiments are shown. Thisinvention may, however, be embodied in many different forms and shouldnot be construed as limited to the embodiments set forth here. Rather,these embodiments are examples of the invention, which has the fullscope indicated by the language of the claims. Like numbers refer tolike elements throughout.

Definitions

For purposes of the present invention, an “organosilicon precursor” is acompound having at least one of the linkages:

which is a tetravalent silicon atom connected to an oxygen or nitrogenatom and an organic carbon atom (an organic carbon atom being a carbonatom bonded to at least one hydrogen atom). A volatile organosiliconprecursor, defined as such a precursor that can be supplied as a vaporin a plasma enhanced chemical vapor deposition (PECVD) apparatus, is anoptional organosilicon precursor. Optionally, the organosiliconprecursor is selected from the group consisting of a linear siloxane, amonocyclic siloxane, a polycyclic siloxane, a polysilsesquioxane, analkyl trimethoxysilane, a linear silazane, a monocyclic silazane, apolycyclic silazane, a polysilsesquiazane, and a combination of any twoor more of these precursors.

Values of w, x, y, and z are applicable to the empirical compositionSi_(w)O_(x)C_(y)H_(z) throughout this specification. The values of w, x,y, and z used throughout this specification should be understood asratios or an empirical formula (for example for a coating or layer),rather than as a limit on the number or type of atoms in a molecule. Forexample, octamethylcyclotetrasiloxane, which has the molecularcomposition Si₄O₄C₈H₂₄, can be described by the following empiricalformula, arrived at by dividing each of w, x, y, and z in the molecularformula by 4, the largest common factor: Si₁O₁C₂H₆. The values of w, x,y, and z are also not limited to integers. For example, (acyclic)octamethyltrisiloxane, molecular composition Si₃O₂C₈H₂₄, is reducible toSi₁O_(0.67)C_(2.67)H₈. Also, although SiO_(x)C_(y)H_(z) is described asequivalent to SiO_(x)C_(y), it is not necessary to show the presence ofhydrogen in any proportion to show the presence of SiO_(x)C_(y).

The term “barrel” refers to a medical barrel, as may be used, e.g., aspart of a medical device for containing and dispensing liquid product,such as a syringe.

The terms “plunger” or “plunger assembly” when used with reference toany embodiment of the present invention (as opposed to with reference toconventional plungers in the art) refers to a convertible plungeraccording to the present invention.

“Frictional resistance” can be static frictional resistance and/orkinetic frictional resistance.

The “plunger sliding force” (synonym to “glide force,” “maintenanceforce”, or F_(m), also used in this description) in the context of thepresent invention is the force required to maintain movement of aplunger tip in a syringe barrel, for example during aspiration ordispense. It can advantageously be determined using the ISO 7886-1:1993test known in the art. A synonym for “plunger sliding force” often usedin the art is “plunger force” or “pushing force”.

The “plunger breakout force” (synonym to “breakout force”, “break looseforce”, “initiation force”, F_(i), also used in this description) in thecontext of the present invention is the force required to initiatemovement of the plunger tip in a syringe, for example in a prefilledsyringe.

Both “plunger sliding force” and “plunger breakout force” and methodsfor their measurement are described in more detail in subsequent partsof this description. These two forces can be expressed in N, lbs or kgand all three units are used herein. These units correlate as follows:1N=0.102 kg=0.2248 lbs (pounds).

“Slidably” means that the plunger tip, closure, storage ring,convertible plunger or other removable part is permitted to slideaxially, e.g. in a medical barrel.

“Container closure integrity” or “CCI” refers to the ability of acontainer closure system, e.g., a plunger disposed in a prefilledsyringe barrel, to provide protection and maintain efficacy andsterility during the shelf life of a sterile product contained in thecontainer.

The term “outward radial pressure,” as used with respect to a plungeraccording to the invention or elements thereof, refers to pressureapplied or exerted in a direction outward from (or away from) theplunger's central axis.

The term “syringe” is broadly defined to include cartridges, injection“pens,” and other types of barrels or reservoirs adapted to be assembledwith one or more other components to provide a functional syringe.“Syringe” is also broadly defined to include related articles such asauto-injectors, which provide a mechanism for dispensing the contents.Optionally, “syringe” may include prefilled syringes. A “syringe” asused herein may also apply to vaccine dispensing syringes comprising aproduct space containing a vaccine. A “syringe” as used herein may alsohave applications in diagnostics, e.g., a sampling device comprising amedical barrel prefilled with a diagnostic agent (e.g., contrast dye) orthe like.

One or two openings, like the openings of a sample tube or vial (oneopening) or a syringe barrel (two openings) are preferred. If the vesselhas two or more openings, they can be of same or different size.

Though the invention is not necessarily limited to syringes of aparticular volume, syringes are contemplated in which the lumen has avoid volume of, for example, from 0.5 to 50 mL, optionally from 1 to 10mL, optionally from 0.5 to 5 mL, optionally from 1 to 3 mL.

“PECVD” refers to plasma enhanced chemical vapor deposition.

A “lubricant” is a material or substance introduced to reduce frictionbetween surfaces in mutual contact. A “flowable lubricant” is alubricant that is deposited on a surface as a fluid (liquid or vapor).This definition encompasses such lubricants that are not treated ormodified upon or after deposition, e.g., PDMS or silicone oil, in liquidform, applied to a surface. This definition also encompasses a liquid orvapor applied lubricant that is condensed, cross-linked, plasma-treated,reacted, heated, irradiated, or otherwise treated or modified upondeposition or subsequent to deposition. A common characteristic offlowable lubricants is that they tend to generate particles, e.g., inthe form of droplets or micelles.

References to “pharmaceutical agent,” “pharmaceutically active,”“pharmaceutical,” “drug,” “medicament,” “active agent,” “active drug,”“drug product” and the like, refer in a general sense to substancesuseful in the medical and scientific arts as suitable for delivery via asyringe, including, for example, drugs, biologics, diagnostic agents(e.g., dyes or contrast agents) or other substances used fortherapeutic, diagnostic, or preventative (e.g., vaccines), or researchpurposes. Example pharmaceutical agents or drug products includebiologics, vaccines, chemotherapeutic agents, contrast agents, smallmolecules, immunogens, antigens, interferons, polyclonal antibodypreparations, monoclonal antibodies, anesthetics, interfering RNAs, genevectors, insulins, or combinations of any of these. “Inactive”substances refer to carriers, excipients, diluents, and the like, whichare well-known in the art, although such substances may have beneficialfunction in the mixed injectable, such as, for example, adjuvants,isotonic or buffering agents. These active or inactive substances mayalso include substances having immediate, delayed or sustained releasecharacteristics. It is contemplated that “drug products” may broadlyinclude active and inactive substances configured for storage andinjection by a syringe.

Syringe Barrel Materials

Optionally, syringes according to any embodiment of the presentinvention may be made from one or more injection moldable thermoplasticmaterials including, but not limited to: an olefin polymer;polypropylene (PP); polyethylene (PE); cyclic olefin copolymer (COC);cyclic olefin polymer (COP); polymethylpentene; polyester; polyethyleneterephthalate; polyethylene naphthalate; polybutylene terephthalate(PBT); PVdC (polyvinylidene chloride); polyvinyl chloride (PVC);polycarbonate; polymethylmethacrylate; polylactic acid; polylactic acid;polystyrene; hydrogenated polystyrene; poly(cyclohexylethylene) (PCHE);nylon; polyurethane polyacrylonitrile; polyacrylonitrile (PAN); anionomeric resin; Surlyn® ionomeric resin. For applications in whichclear and glass-like polymers are desired (e.g., for syringes andvials), a cyclic olefin polymer (COP), cyclic olefin copolymer (COC) orpolycarbonate may be preferred. Such materials may be manufactured,e.g., by injection molding or injection stretch blow molding, to verytight and precise tolerances (generally much tighter than achievablewith glass). Alternatively, syringes according to embodiments of thepresent invention may be made from glass.

Syringe and Convertible Plunger Embodiments

In FIG. 1, one exemplary embodiment of a syringe 10 including a plungerassembly 20 constructed in accordance with one aspect of this inventionis shown. As a brief aside, the terms “distal” and “proximal” are usedthroughout this specification. The terms “distal” and “proximal” refergenerally to a spatial or positional relationship relative to a givenreference point, wherein “proximal” is a location at or comparativelycloser to that reference point and “distal” is a location further fromthat reference point. As applied herein to syringe barrels, for example,the relevant reference point is the back end of the barrel (for example,the flange at the top of the barrel 12 as shown in FIG. 1), near wherethe plunger rod 22 and the convertible plunger 24 are joined. The distalend is at the bottom or dispensing end of the barrel 12, where theneedle 18 is mounted. “Proximal” and “distal” may also be used to referto the direction of application of force. For example, the pushing forceto dispense syringe contents would be applied in a “distal direction” or“distally,” i.e., a force pushing the plunger head 30 down in FIG. 1 toadvance the liquid sealing section 36 down toward the dispensing end ordistal end of the syringe.

The syringe 10 is of generally conventional construction and includes ahollow barrel 12 having a central longitudinal axis A. The barrel has aninner surface 14 and is configured to hold an injectable liquid 16therein. A needle 18 is located at the distal end of the barrel and isin fluid communication therewith. The plunger assembly 20 is disposed sothat a distal portion of it is located in the proximally located portionof the barrel, like shown in FIG. 1, whereupon the syringe 10 is readyfor use. To that end, when the plunger assembly 20 is actuated, e.g.,pushed in the distal direction, it forces the injectable liquid withinthe barrel out through the needle 18.

The plunger assembly 20 basically comprises a plunger rod 22 and aconvertible plunger 24. The convertible plunger 24 constitutes asubassembly of components which are configured to provide sufficientcompressive force against the inner surface of the sidewall of aprefilled syringe or cartridge barrel to effectively seal and preservethe shelf-life of the contents of the barrel during storage. When aconvertible plunger, such as that of the subject invention, providescontainer closure integrity (CCI) and gas-tight sealing (e.g., providinga barrier to oxygen, moisture and/or optionally additional gases),adequate to effectively seal and preserve the shelf-life of the contentsof the barrel during storage, the convertible plunger (or at least aportion of its exterior surface) may alternatively be characterized asbeing in an “expanded state” or “storage mode.” The expanded state orstorage mode may be a product of, for example, an expanded outerdiameter or profile of at least a portion of the syringebarrel-contacting surface of the plunger and/or the normal force thatthe plunger exerts on the inner wall of the syringe barrel in which itis disposed. The convertible plunger (or at least a portion of itsexterior surface) is reducible to what may alternatively becharacterized as a “constricted state” or a “dispensing mode,” whereinthe compressive force against the sidewall of the barrel is reduced oreliminated in part, allowing a user to more easily advance the plungerin the barrel and thus dispense the contents of the syringe orcartridge. The constricted state or dispensing mode may be a product of,for example, a reduced outer diameter or cross-sectional width (relativeto that of the expanded state) of at least a portion of the syringebarrel-contacting surface of the plunger and/or reduced normal forceagainst the inner wall of the syringe barrel exerted by the plungerand/or reduced resistance to inward radial compression.

As used herein, the term “convertible plunger” broadly includes aplunger, configured for use in a medical barrel, wherein the plunger isconvertible from a storage mode to a dispensing mode, as generallydescribed above. This specification focuses primarily (albeit notexclusively) on convertible plunger embodiments having a liquid sealingsection that translates axially in a medical barrel, independently of aseparate storage sealing section component, when the plunger transitionsfrom storage mode to dispensing mode (for short, “independent storagesealing section plunger”). An alternative type of convertible plunger,which is the subject of applications assigned to the same assignee asthe present Application, is optionally described as having an insertpositioned within a cavity of the plunger sleeve to provide outwardradial pressure of an adjacent storage sealing section against a medicalbarrel wall (to provide a storage mode). The insert, which is preferablymore rigid than the plunger sleeve, is then movable to a differentcavity (e.g., a cavity that is distal to the storage cavity) within theplunger sleeve to release such radial compression and thus transitionthe plunger to a dispensing mode. Such “insert and sleeve” plungers aredescribed in PCT Publication No. WO 2015/054282, which is incorporatedby reference herein in its entirety. While insert and sleeve plungersare not the primary focus of the present application, some embodimentsare described herein particularly to illustrate methods and apparatus,according to aspects of the invention, for assembling such plungers intomedical barrels. It should be understood, moreover, that the invention,in one aspect, may cover at least both independent storage sealingsection and insert and sleeve types of convertible plungers.

Features common to both the independent storage sealing section type ofplunger and insert and sleeve type of plunger are as follows. Generallyspeaking, they both comprise an internal portion and a generallycylindrical exterior surface that surrounds at least part of theinternal portion. The generally cylindrical exterior surface includes acompressible and resilient storage sealing section (optionally anelastomer) that is maintained in an expanded state by outward radialpressure provided by the internal portion. The internal portion iscomparatively more rigid than the storage sealing section. The expandedstate is reducible to a constricted state by an operation that isapplied to the internal portion of the plunger to reduce or eliminatethe outward radial pressure. The storage sealing section, in theconstricted state, has a reduced maximum diameter or cross-sectionalwidth than the storage sealing section in the expanded state and/or isless resistant to inward radial compression compared to the storagesealing section in the expanded state. With the insert and sleeve typeplunger, the internal portion comprises the insert and storage sealingsection is the portion of the sleeve surrounding and adjacent to theinsert. With the independent storage sealing section plunger type, theinternal portion is the ring carrier and the storage sealing section ison the storage ring. In both cases, the plungers are preferably actuatedby applying a force to the plungers in a distal direction. Suchactuation force may apply the aforementioned operation to the internalportion of the plunger. In the case of the insert and sleeve typeplunger, the operation may displace the insert from a proximal cavity toa distal cavity in the sleeve. In the case of the independent storagesealing section plunger type, the operation includes axial displacementof the ring carrier relative to the storage ring when transitioning fromstorage mode to dispensing mode.

Accordingly, in one aspect, as shown in FIGS. 1 and 2A-3B, the inventionis a convertible plunger 24 comprising a central core 32 having alongitudinal axis which is coaxial with the central axis A of the barrel12, a storage sealing section 34 and a liquid sealing section 36. Thecentral core 32 is preferably rigid, optionally made from a polymermaterial. The storage sealing section 34 and the liquid sealing section36 each have a respective generally cylindrical exterior surface. Asused herein, a “generally cylindrical” exterior surface may includeminor interruptions or variations in geometry (e.g., due to ribs,valleys, etc.) to the otherwise cylindrical shape of the externalsurface of a given component, e.g., the liquid sealing section. As willbe described in detail later, the generally cylindrical exterior surfaceof the storage sealing section includes one or more annular ribs oroutwardly projecting surfaces for engagement with the inner wall of thesyringe barrel when the storage sealing section is in its expandedstate. The expanded state is reducible to a constricted state by therelative movement of the storage sealing section along the longitudinalaxis A with respect to the liquid sealing section or vice versa. As usedherein, “expanded state” and “constricted state” may refer tocomparative dimensional measurements (e.g., expanded state being widerthan constricted state) and/or comparative resistance to inwardcompression of the plunger (the “expanded state” being more resistant toinward compression and the “constricted state” being less resistant toinward compression) and/or comparative outward radial pressure exertedby at least a portion of the plunger's exterior surface (the plunger'sexterior surface in the “expanded state” exerting more outward radialpressure and in the “constricted state” exerting less outward radialpressure).

The convertible plunger 24, preferably at a proximal end of the centralcore 32, is mounted on a distal end of the plunger rod 22. The plungerrod 22 is an elongated member having a central longitudinal axisextending coaxially with the central axis A of the barrel of thesyringe. The distal end of the plunger rod is optionally in the form ofa threaded projection 26 (FIG. 2A) extending distally from the distalend of the rod 22 and centered on the axis A. The threaded projection 26is configured to be threadedly received within a mating threaded bore orhole 28 in the proximal end of the convertible plunger 24 to mount theconvertible plunger on the distal end of the plunger rod 22.Alternatively, the plunger 24 may be mounted to the distal end of theplunger rod 22 through other means, such as by snap fit or press fit.The proximal end of the plunger rod 22 is in the form of an enlargedflanged head 30 (FIG. 1), which is configured to be pressed by a user toeject the liquid 18 from the syringe.

The convertible plunger 24 is configured for operating in two modes. Onemode is a sealing mode, like shown in FIGS. 1 and 2A, in which thestorage sealing section 34 of the plunger is in its “engagement”position wherein it is compressed between a first portion of the centralcore of the plunger and the internal wall of the syringe's barrel toform a gas-tight, liquid-tight and CCI level interface therebetween. Theother mode is a gliding mode in which the storage sealing section isshifted to a different portion on the central core, e.g., a “release”position, when the plunger assembly is slid in the barrel so that thestorage sealing section is no longer in engagement (or is in reducedengagement) with the internal wall of the barrel. However, in thegliding mode the liquid sealing section of the plunger will be insliding engagement with the internal wall of the barrel to form aliquid-tight interface therebetween. Moreover, owing to the inherentlubricity of liquid sealing section, no liquid or other flowablelubricants (e.g., silicone oil) are necessary to be used between theplunger and the barrel to facilitate sliding of the plunger in thebarrel. This feature constitutes a considerable advantage over the priorart, since the use of a flowable lubricant between the plunger and thebarrel to facilitate sliding of the plunger may have the effect ofcontaminating the injectable liquid if the lubricant disassociates fromthe syringe or plunger into that liquid. The liquid sealing sectionitself, in addition to providing a liquid tight seal, preferably alsoprovides a CCI-level seal, to comply with prevailing industry concernsand to provide CCI redundancy with the storage sealing section.

As best seen in FIGS. 2A-2C, the liquid sealing section 36 is mounted onthe distal end of the plunger's central core 32, while the storagesealing section 34 is located proximally of the liquid sealing section.The storage sealing section 34 is in the form of at least one ringmounted around a portion of the central core and configured so that whenthe plunger assembly is in the engagement position like shown in FIGS. 1and 2A, the at least one ring of the storage sealing section 34 formsthe heretofore mentioned liquid-tight and gas-tight interface with theinterior wall 14 of the syringe's barrel 12. Thus, when the plungerassembly is in that position the storage sealing section provides CCIand a gas-tight seal for the syringe. In the exemplary embodiment shownin FIG. 1 the storage sealing section is in the form of a single“O-ring” 38 of circular cross-section. Other single rings of variouscross-sectional shapes may be provided to form the storage sealingsection. In fact, multiple rings of various cross-sectional shapes maybe provided to form the storage sealing section. For example,optionally, the O-ring has more than one rib or lobe; e.g., 2 ribbed or3 ribbed O-rings are contemplated. Some of those alternative embodimentsfor the storage sealing section are discussed below.

The central core 32 of the convertible plunger 24 is an elongated rigidmember, optionally having a cylindrically shaped mounting projection 40at the distal end thereof. The projection 40 can be of any suitableshape. In the exemplary embodiment shown it is semi-spherical. Theprojection 40 serves as the means for mounting the liquid sealingsection 36 on the distal end of the central core 32. A flange 42projects radially outward from the central core immediately proximallyof the projection 40. An annular storage platform 44 is provided on thecentral core 32 immediately proximally of the flange 42. The storageplatform 44 is configured to receive and hold the at least one ring 38thereon in a “holding” position when the plunger assembly 24 is in thestorage mode, i.e., the state shown in FIG. 1.

The ring 38 is formed of a resilient material or one or more resilientmaterials, including, but not limited to, a thermoset rubber (e.g.,butyl rubber), a thermoplastic elastomer (TPE), liquid silicone rubberand fluoro-liquid silicone rubber. The diameter of the central core 32at the location of the storage platform 44 is greater than the normalinternal diameter of the ring 38. Thus, when the ring 38 is disposedaround the storage platform 44 it is stretched from its normal outerdiameter (i.e., its “constricted” state) to its “expanded” state. Inthat expanded state the outermost portion of the periphery of the ringwill be in intimate engagement with the inner surface 14 of the barrel,thereby forming the heretofore mentioned gas-tight, CCI-tight andliquid-tight interface therebetween. As should be appreciated by thoseskilled in the art, when the ring 38 is in such engagement with theinner surface of the barrel “sticktion,” can result. Thus, theconvertible plunger of this invention is constructed to enable thecentral core 32 to move with respect to the ring 38 (which initiallyadheres to the barrel through sticktion) to enable the plunger assembly24 to be moved to the release position wherein it operates in theheretofore mentioned gliding mode. When in that mode, the ring 38 willbe in a constricted state, wherein the outside diameter of the ring isoptionally less than the inner diameter of the interior surface 14 ofthe barrel's wall 12 so that the ring does not engage that interiorsurface and hence will not interfere with the sliding movement of theplunger assembly into the barrel.

In order to enable the O-ring 38 to move from its engagement position(wherein it will be retained about the storage platform 44) to therelease position (wherein it is transitioned from the storage platform44), the central core 32 includes a conically tapering section 46located immediately adjacent the storage platform 44. The proximal endof the conically tapering section 46 terminates in a cylindrical section48, the external diameter of which is less than the external diameter ofthe storage platform 44. Thus, when the plunger assembly 20 is pressedto cause it to move in the distal direction (i.e., applying an operationto the internal portion of the plunger comprising application of anactuation force on the plunger in the distal direction) shown by thearrow in FIG. 2A within the barrel 12, the frictional engagement betweenthe O-ring and the inner wall of the barrel will tend to hold the O-ringat that longitudinal position in the barrel, while the central core 32moves distally. In other words, the O-ring 38 preferentially adheres tothe inner surface 14 of the barrel over the outer surface of the centralcore 32. Thus, there will be relative movement between the O-ring 38 andthe central core 32 in the axial direction. That relative axial movementcauses the O-ring 38 to move from its holding position about the storageplatform 44, so the O-ring slides in the proximal direction with respectto the central core 32 in the direction of the arrows 50 in FIG. 2A,whereupon the radially outer-most surface of the O-ring will no longerbe in engagement (or optionally will be in reduced engagement or applyreduced outward radial pressure) with inner surface 14 of the barrel. Assuch, the plunger assembly 20 can be slid smoothly down the barrel withminimal force. Continued pressing of the plunger assembly distally willultimately bring the O-ring into engagement with the undersurface of aprojecting flange 52 forming the proximal end of the central core 32,such as shown in FIG. 2C.

As mentioned above, when the plunger assembly 20 is in the glide mode,the liquid sealing section 36 will be in sliding engagement with theinner surface 14 of the barrel to result in a good liquid-tightinterface therebetween. To that end, the liquid sealing section 36basically comprises an elastomeric body or head 54 having an exteriorsurface portion having a lubricity that is greater than the lubricity ofthe interior wall 14. The first surface portion may be in the form of afilm 56 which extends about the entire exterior surface of the head 54.The film may have an optional thickness in any embodiment of underapproximately 100 micrometer (μm), optionally from 25-50 μm. A varietyof different materials may be employed for the film, such as, forexample, an inert fluoropolymer, including, fluorinated ethylenepropylene (FEP), ethylene tetrafluoroethylene (ETFE),polytetrafluoroethylene (PTFE), ethylene perfluoroethylenepropylene(EFEP), ethylene chlorotrifluoroethylene (ECTFE),Polychlorotrifluoroethene (PCTFE), perfluoroalkoxy (PFA), among othercoatings. Optionally, CPT fluoropolymer may be used. CPT is a modifiedperfluoroalkoxy (PFA) commercially available from Daikin America, Inc.and generally comprises the addition of PCTFE side chains to a PFA mainchain during polymerization, thereby increasing gas and/or liquidbarrier properties of standard PFA. Optionally, the exterior surface ofthe head 54 may be in the form of a rigid cap (not shown) formed of aperfluoropolyether oil, such as DEMNUM which is commercially availablefrom Daikin America, Inc., which may be mixed with resin and extrudedinto a film, mold or cap. Additionally, according to certainembodiments, the material used for the film coating may not be anexpanded fluoropolymer. Further, according to certain embodiments,additives may be added to the material for the film or cap, such asadditives that may improve the adhesion of the film or cap to theunderlying portion of the plunger making up the liquid sealing sectionand/or decrease the friction between that section and the sidewall ofthe barrel. Additionally, according to certain embodiments, an adhesionpromoting coating or process may be employed, such as, for example, acorona treatment. For some applications, it may be desirable tocoextrude different materials to form the film. For example, coextrudedfilm combinations may include a cyclic olefin copolymer (COC) withAclar, Polyethylene (PE) with Aclar and FEP with PE, among othercombinations.

Optionally, after the film material has been inserted into the mold, theplunger material is injected into the mold. Thus, in the final product,the liquid sealing section of the plunger may comprise a plunger core, apolymer head disposed on the tip of the plunger core and a film coveringthe head. Alternatively, a high durometer, lubricious TPE materialwithout any film disposed thereon may be used as the liquid sealingsection.

In the case where a film 56 is used to provide the lubricious outersurface of the liquid sealing section, the film may be secured to thehead 54 in various ways. For example, as shown in FIG. 3A a sheet offilm 56 may be wrapped about the head 54, so that the portions 58 of thesheet of film contiguous with its edges are located within a recess 60in the head 54, like shown in FIGS. 2A-2C and 3A. The recess 60 is of amating shape to the shape of the projection 40. Thus, when theprojection 40 is inserted into the recess to mount the head 54 on thedistal end of the central core 32, the edge portions 58 of the film 56will be trapped therein. The securement of the head 54 to the centralcore 32 can be achieved by means of a press fit, compression ribs, orany other suitable means for fixedly securing the head to the centralcore with the edge portions of the film trapped therebetween.

FIGS. 4A and 4B illustrate another convertible plunger 124 constructedin accordance with this invention. The plunger 124 basically comprises acylindrical central core 132 having a distal end 135 to which a head 154is fixedly secured. The head 154 is similar to the head 54 and serves toform a portion of the liquid sealing section 136 of this embodiment. Asheet of film 156, similar to the film 56 described above is wrappedabout the head 154, with the portions of the film at its edges beingtrapped between the core 132 and a cylindrical sleeve 160. The sleeve160 is an elongated rigid tubular member, the inside diameter of whichis just slightly larger than the outside diameter of the central core132. The inner surface of the sleeve at its distal end includes anannular inner recess 162. The outer surface of the sleeve at its distalend includes an annular storage platform 144. The inner recess 162 isconfigured to receive and trap the edge portions of the film 156. Thestorage platform 144 is similar in function to the storage platform 44,i.e., it is arranged to receive and hold the storage sealing section 134of the convertible plunger 124 when the plunger 124 is in storage mode.That storage sealing section 134 comprises a ring 138 formed of asimilar material as the O-ring 38, but the ring 138 has a generallyrectangular cross-section with a slightly concave outer surface 140. Thetop and bottom edges of the outer surface 140 of the ring 138 are in theform of a pair of annular ribs 142, each of which forms an engagementsurface to tightly engage the inner surface of the barrel when a plungerassembly composed of the convertible plunger 124 is located within thebarrel 12 of the syringe in the engagement position. That engagementresults in a good gas-tight and liquid-tight interface between the ring138 and the inner surface of the barrel.

The ring 138, like the O-ring 38, is arranged to be moved from theengagement position to the release position, whereupon it no longerengages the inner surface of the barrel. To that end, the sleeve 160includes a conically tapering section 146 located immediatelyproximately of the storage platform 144. The proximal end of theconically tapering section 146 terminates in a cylindrical section 148,the external diameter of which is less than the external diameter of therecess 144. Thus, when the plunger assembly including the convertibleplunger 124 is pressed to cause it to move in the distal directionwithin the barrel 12 of the syringe, the O-ring 138 will move from thestorage platform 144 and slide in the proximal direction with respect tothe central core, whereupon the ribs 142 of the ring 138 will no longerbe in engagement with (or at least will be in reduced engagement with)the inner surface 14 of the barrel. As such, the plunger assembly can beslid smoothly down the barrel with minimal force. The liquid sealingsection of the convertible plunger 124 operates in the same manner asdiscussed with reference to the convertible plunger 24, and hence willnot be reiterated in the interest of brevity.

In order to facilitate the assembly of the components making up theconvertible plunger 124, the central core 132 includes a plurality ofelongated venting grooves or channels 170 extending longitudinallytherealong and being equidistantly spaced about the periphery of thecentral core. The grooves or channels 170 enable any air that would betrapped between the sleeve 160 and the central core 132 when the sleeveis mounted on the central core to exit or vent out the bottom of thesleeve. Alternatively, the venting slots or channels may be provided inthe inner surface of the sleeve 160 rather than the outer surface of thecentral core 132. In fact, the venting slots may be provided in both theinner surface of the sleeve and the outer surface of the central core.In any case, by venting any air between the sleeve and the central coreone is able to trap the edge portions of the film 156 between the sleeveand the central core within the inner annular recess 162 expeditiouslyand neatly.

Still another embodiment of a convertible plunger is shown in FIGS. 5Aand 5B and will be discussed now. That convertible plunger is designatedby the reference number 224 and is similar in construction to theplunger 24 described heretofore, except for the manner in which the edgeportions of the film 56 are trapped with respect to the central core soas not to be exposed. In the interest of brevity those features of theconvertible plunger 224 which are common to the convertible plunger 24will be given the same reference numbers and the details of theirconstruction and operation will not be reiterated. Thus, as can be seen,the convertible plunger 224 includes a central core 32 on which thestorage sealing section 34 and the liquid sealing section 36 aremounted. The portions of the film 56 contiguous with the edges thereofare not, however, trapped between the projection 40 and the recess 60 inthe head 54. Instead those edge portions are trapped between a retainerring 162 and the flange 42. The retainer ring is formed by molding itabout the edge portions of the sheet of film 56. To that end, a moldmember 170 having an annular cavity 172 of generally L-shape incross-section is disposed about the portion of the central core 32 atthe location of the flange 42, with the edge portions of the sheet offilm 56 located within the cavity 172. Then any suitable plasticmaterial is injected into the cavity 172 to form the retaining ring 162.Once that has been accomplished the mold member 170 can be removed,leaving the edge portions of the film trapped under the retaining ringand hence not exposed.

FIGS. 7-9 show three alternative configurations for applying film toplungers according to any embodiment of the invention. The film in theseconfigurations would function the same as film applied in otherconfigurations disclosed herein; so much of the disclosure elsewhere inthe specification suffices for purposes of describing the embodiments ofFIGS. 7-9 and will not be repeated, for the sake of brevity.Differences, however, are noted here. To minimize the chances of filmwrinkling when wrapping the film 56 about the head 54, the film may becut into a pattern enabling it to fold neatly into the recess 60 in thehead 54. Optionally, a rigid polymer support 61 is disposed within therecess 60 to provide a mating surface with portions of the film 56. Asshown in FIG. 7, portions of the film 56 bend into the rigid polymersupport 61 and are sandwiched between the core 32 and the rigid polymersupport 61. Optionally in any embodiment, the film mates with the rigidpolymer support 61 via ultrasonic welding or an adhesive.

In the plunger embodiments shown in FIGS. 8 and 9, the rigid polymersupport 61 has an annular rim 61 a that extends outward towards theouter diameter of the head 54. The core 32 also includes a radiallyextending annular rim 32 a. The rims 32 a and 61 a are configured tomate to one another. As shown in FIG. 8, the rim 32 a on the core 32includes a plurality of radially spaced micro needles 63, adapted topierce the film 56 section covering the rim 61 a and stake into the rim61 a. Thus, when assembled, the film 56 is sandwiched between the rims32 a, 61 a and secured to the head 54. The configuration in FIG. 9 issimilar to that of FIG. 8, except that the rim 32 a on the core 32includes a plurality of radially spaced protrusions 63 adapted to matewith a plurality of radially spaced receptacles 65 on the flange 61 a,thereby securing the film 56 to the head 54. Ribs or grooves can beincorporated on the core or rigid polymer support to provide frictionfor holding the core and for venting, as described elsewhere in thisspecification regarding other embodiments. An optional advantage toincluding a rigid polymer support 61 is that it allows for the option ofultrasonic welding or staking the components.

Referring now to FIGS. 10-12, there is shown an alternative embodimentof a convertible plunger 324 according to an aspect of the presentinvention. The convertible plunger 324 is, to some extent, structurallyand functionally similar to the plunger 24 of FIGS. 1 and 2A-3B,although there are important differences. Like its counterpart in FIGS.1 and 2A-3B, the convertible plunger 324 is configured for operating insealing mode (wherein the storage sealing section in an engagementposition) and gliding mode (wherein the storage sealing section isshifted to a release position), substantially as described above. Also,the convertible plunger 324, like the plunger 24 of FIGS. 1 and 2A-3B,is of the independent storage sealing section plunger type. Further, theplunger 324 may be secured to a plunger rod to form a plunger assembly,e.g., much like the embodiment of the assembly 20 shown in FIG. 1. Forthe sake of brevity, similar features as between the two embodiments(e.g., material of storage ring, the manner in which the plunger issecured to a plunger rod, the basic function of the plunger etc.) willnot be discussed in great depth here. However, differences may be noted.

The convertible plunger 324 comprises a rigid central core 332, whichwould be coaxial with the central axis of a syringe barrel whenassembled into a syringe (e.g., the syringe barrel 12 of FIG. 1). Thecentral core 332 is preferably made from a rigid injection moldablethermoplastic polymer, more preferably from a polyolefin such aspolypropylene (PP), cyclic olefin copolymer (COC) or cyclic olefinpolymer (COP). The liquid sealing section 336 is mounted on the distalend of the plunger's central core 332, while the storage sealing section334 is located proximally of the liquid sealing section 336. The storagesealing section 334 is provided in the form of a unitary storage ring338 mounted on a portion of the central core 332. The central core 332in this embodiment (and others disclosed herein) functions as a rigidring carrier, which is preferably more rigid than the ring 338. Thestorage ring 338 comprises an inner surface 339 facing generallyradially inward toward the central core 332 and an outer surface 341facing generally radially outward away from the central core 332.Preferably, when the storage ring 338 is in an uncompressed state, theinner surface 339 is symmetrical about a plane of symmetry across thewidth W338 (between proximal and distal ends) of the storage ring 338.Also, when the storage ring 338 is in an uncompressed state, the outersurface 341 is preferably symmetrical about a plane of symmetry acrossthe width W338 of the storage ring 338. This symmetrical configurationprovides stability to the storage ring 338 when the convertible plunger324 is in storage mode and when the plunger 324 transitions todispensing mode. A non-symmetrical configuration could result in thering tilting or wobbling axially, potentially compromising the ring'ssealing function and its ability to facilitate the plunger's smoothtransition from storage mode to dispensing mode. While servingessentially the same purpose as the O-ring 38 of convertible plunger 24,the storage ring 338 of convertible plunger 324 is not round incross-section and thus is more appropriately referred to as a storagering (indicating its basic function and structure), rather thanspecifically as an O-ring (referring to a storage ring having agenerally round cross-sectional structure, such as shown in FIGS. 1 and2A-3B). An O-ring is merely a type or shape of storage ring.

The outer surface 341 of the storage ring 338 in the illustratedembodiment (FIGS. 10-12) includes three hills or ribs 338 a, wherein themiddle rib is separated from neighboring ribs 338 a by valleys 338 b oneither side of the middle rib. Multiple ribs 338 a are configured toprovide redundancy in storage sealing. An additional consideration isthat change in pressure within a syringe (e.g., during transport at highaltitudes) may cause an air bubble in the liquid contents of the syringeto compress or expand, causing a plunger to slightly move. Multiple ribs338 a on the storage ring 338 helps to reduce the risk that the plunger324 will move into an unsterile area of the syringe. Optionally, thecontours of the inner surface 339 are mirror images of the contours ofthe outer surface 341 of the storage ring. For example, the ribs 338 aon the outer surface 341 are directly opposed by corresponding ribs 338c on the inner surface 339 located 180° from the ribs 338 a.

Notably, the storage ring 338 is configured to provide, when in theengagement position, a gas-tight seal between both: (1) the storage ring338 and the syringe barrel; and (2) between the inner surface of thestorage ring 338 and the central core 332 (the same applies to theO-ring 38 and the syringe barrel 12 and central core 32 of FIGS. 1 and2A-3B). The storage ring 338 is configured to optimize the sealing andreleasing of the seal and minimize or preferably prevent unintendedcontact with the syringe barrel's inner surface as the plunger travelsdown the barrel during dispensing of syringe contents. The durometer ofthe rubber of the storage ring 338 may factor in to such optimization.

It is further preferred that the storage ring 338 preferentially adhereto the syringe barrel over the central core 332 or ring carrier. This isto ensure that the seal between the storage ring 338 and central core332 releases first (while the storage ring 338 initially continues toadhere to the barrel), allowing the storage ring 338 to move to anunsealed position so that the convertible plunger 324 smoothlytransitions to glide mode. Preferential adherence of the storage ring338 to the syringe barrel also advantageously resists movement of theplunger 324 towards the proximal (and potentially unsterile) end of thesyringe. Preferential adherence of the storage ring 328 to the syringebarrel may optionally be achieved, e.g., with a flowable lubricantcoating on the central core 332. Such lubricants may include, e.g., PDMSin the form of free silicone oil, cross-linked silicone oil (e.g.,through plasma cross-linking), or baked on silicone. Alternatively, thecentral core 332 may be coated with or embedded with fluorinatedlubricants, e.g., Teflon, parylenes or any fluorinated polymer disclosedherein for use as a plunger film or cap material. Alternatively, thecentral core 332 may be provided with a lubricity coating applied byplasma enhanced chemical vapor deposition (PECVD), optionally usingoctamethylcyclotetrasiloxane (OMCTS) as a precursor. Such a coating mayhave the chemistries of a pH protective coating or a lubricity coatingas described in U.S. Pat. No. 7,985,188, which is incorporated herein byreference in its entirety. Any of the aforementioned lubricating meansmay be provided between the storage ring and the ring carrier tofacilitate sliding of the storage ring axially along the ring carrierwhile the ring preferentially adheres to the interior wall of themedical barrel. Notably, however, it is highly preferred that neitherthe medical barrel-contacting surfaces of the plunger 324 (storagesealing section 334 and liquid sealing section 336) nor the innersurface of the medical barrel are coated with flowable lubricant such asfree silicone oil. In this preferred aspect of the invention, theconvertible plunger 324 provides an “oil-free” solution for prefilledsyringe applications, which is advantageous for reasons explained above.

The central core 332 is an elongated rigid member comprising, from thedistal end thereof, a flange 342 which projects radially outward fromthe central core 332. Proximal to the flange 342 is an annular storageplatform 344, which supports the storage ring 338 when the plunger 324is in storage sealing mode. Proximal to the storage platform 344 is aconically tapering section or gradual transition region 346 whichterminates in a cylindrical section or dispensing platform 348, theexternal diameter of which is less than that of the storage platform344. The dispensing platform 348 terminates at a flange 352.

The convertible plunger 324 operates largely in the same way as itscounterpart in FIGS. 1 and 2A-3B to transition from storage sealing modeto a dispensing mode. These details will be summarized here in thecontext of the plunger 324 of FIGS. 10-12. As shown in FIGS. 10-12, thestorage ring 338 is disposed on the storage platform 344. In thisposition, the storage ring 338 is configured to provide sufficientcompression against a medical barrel in which it is disposed, so as toprovide a gas-tight and liquid-tight seal, thus providing CCI andprotecting sterility of the barrel's contents over a desired shelf life.At the time of actuation/use, when plunger 324 begins to advance in adistal direction in a medical barrel, the central core 332 slidesdistally with respect to the storage ring 338, causing the ring 338 totransition to the conically tapering section or gradual transitionregion 346 and then ultimately end at the dispensing platform 348. Thegradual transition region 346 is shown in a conical shape, but may be inother configurations, e.g., curved.

When disposed on the dispensing platform 348, the storage ring 338provides either reduced compression or no compression whatsoever againstthe medical barrel, thus putting the plunger 324 in dispensing mode. Theflange 352 catches the storage ring 338, preventing it fromdisassociating itself from the proximal end of the central core 332.This also blocks plunger movement in a proximal direction in the eventthe storage ring fails to release from the barrel, thus reducing therisk of the storage ring 338 contacting an unsterile area within thesyringe barrel.

As mentioned above, the liquid sealing section 336 is disposed on theplunger 324 distal to the flange 342 and storage sealing section. Theliquid sealing section 336 provides a liquid-tight seal with the barrelsidewall and preferably also provides CCI for barrel contents. Theliquid sealing section 336 optionally comprises a head 354 having a film356 wrapped thereon, as substantially described above with respect toother embodiments. As shown in FIG. 12, the head 354 comprises aresilient material such as an elastomer 355 that is disposed over arigid support 361, preferably a polymer support. The rigid support 361advantageously provides a rigid surface to secure or bond the liquidsealing section 336 to the central core 332. The rigid support 361 mayinclude a stem 363 that is secured within a central mating recess 360 ofthe central core 332, e.g., by ultrasonic welding, an adhesive, apress-fit, a snap-fit or through threaded engagement. Particularly ifultrasonic welding is used, the rigid support 361 is preferably the samematerial as the central core 332 (e.g., a desired polyolefin).Optionally, the film 356 edge terminates within the central matingrecess 360 of the central core 332 and is secured therein, rendering thefilm edge unexposed after assembly, thus strengthening the bond betweenthe film 356 and the head 354.

Optionally, the head 354 may be made through two-shot injection molding,wherein a first shot injects the rigid support 361 within a mold and thesecond shot injects the elastomer 355 within the mold, or vice versa.Such a method advantageously avoids the need for assembling separatecomponents to make the head 354. If a two-shot molding process is used,the materials must be compatible to enable the elastomer 355 and rigidpolymer support 361 to bond together, thus forming a unitary structure.For example, if the elastomer 355 is a polyolefin based thermoplasticelastomer, the rigid support 361 is preferably a polyolefin, such as PP,COP or COC.

This plunger configuration provides several advantages. For example, thefilm 356 may be wrapped tightly over the head 354 without distorting theshape of the film or head, due to the rigid internal structure.Moreover, the rigid central core 332 facilitates automation, while stillproviding an elastomer 355 that is sufficiently resilient enough toprovide adequate liquid sealing. In addition, this constructionminimizes the amount of elastomeric material that may be subject tocompression setting.

Optionally, the film may be wrapped about the plunger head according tothe following process. The process comprises any combination of one ormore of the following steps: (a) optionally loading film onto rollers;(b) optionally loading a plunger head in tooling; (c) optionally heatingthe film to a temperature for a length of time configured to render thefilm formable into a preform, wherein the controller is optionally setto heat the film to very high temperature (e.g., a controller set pointof at least 1000° C., preferably above 1200° C., optionally about 1275°C.); (d) optionally applying a vacuum to pull film into preform tooling,wherein the preform is smaller than the plunger head; (e) optionallycutting out a film disk with the preform and transfer the disk to aforming station; (f) optionally clamping the cut disk with the preformrigidly at the perimeter, inverting the preform using a vacuum and pushthe plunger head up through the inverted preform stretching the preformto conform to the plunger head; (g) optionally pushing the plunger headand preform through an opening to gather the excess film behind theplunger head, holding film and plunger head on circumference with afirst gripper and clamping the excess film behind the plunger head witha second gripper and rotating the first gripper at least 180°,optionally at least 270°, optionally up to about 720° rotation, whereinsuch rotation tightens the film about the plunger head; (h) optionallytrimming the excess film away and rotating the plunger head to break theplunger free from the film; and (i) optionally finishing the film edgeby using a heated tamping die to tamp cut the edge to back surface ofthe plunger head. This process is an alternative to traditional methodsof laminating the film during a molding process.

Dimensions of the plunger may vary depending on specific needs,applications and syringe barrel diameters. Applicants have found thatcertain specific dimensions may be advantageous. The plunger head 354needs to provide a liquid tight seal to prevent liquid contents of thesyringe from leaking past the plunger head 54, a phenomenon Applicantsrefer to as “blowback.” An embodiment with a sealing height H336 of theliquid sealing section 336 of 3.0 mm and a diameter of 6.50 mm in a 6.48mm syringe underwent testing, described in Example 2, below. Thatembodiment successfully blocked a 40 N load, without any leakage,wherein that load was applied distally, i.e., in a direction fordispensing liquid contents (although the needle was blocked to preventthe liquid from exiting the syringe). Also, Applicants have found thatthe wall thickness T355 of the elastomer 355 of the plunger head 354impacts glide force. For example a T355 of 1.00 mm has a higher glideforce than a T355 of 1.45 mm. Also, Applicants have found a rigidsupport width W361 of 3.7 mm to be beneficial for some applications.

Optionally, an alternative geometry is shown in FIG. 12A, which aims toreduce the interference area between the liquid sealing section andsyringe barrel. FIG. 12A illustrates a height of 0.75 mm at the maximumdiameter.

Preferably, a liquid sealing section may be configured, according to anaspect of the invention, to provide a CCI level of sealing, although notgas (e.g., oxygen) sealing.

As discussed herein, the terms “central core” (e.g., 32 or 332) or“sleeve” (in the case of the sleeve 160 of the embodiment shown in FIGS.4A and 4B), have a storage ring or O-ring disposed directly thereon. Thecentral core, sleeve or any other element on which the ring or storagesealing section is disposed may be referred to herein generically as a“ring carrier.” The ring carrier, in whichever form it takes, should berigid. A rigid ring carrier provides necessary support and dimensionaltolerances for the storage ring to reach desired and precise levels ofcompression when the plunger is in storage mode and to release smoothly(with little to no perception to the user) when the plunger transitionsto dispensing mode. It should be borne in mind that the storage ring andthe plunger in general will typically be tiny. Since the plungercomponents need to operate smoothly in what is typically asmall-diameter syringe barrel, tight dimensional tolerances are needed.A rigid ring carrier does not compress when the storage ring disposedthereon compresses. In this way, the storage ring is the only variablethat must be accounted for in designing a ring that is configured toprovide an adequate seal on the one hand when the plunger is in storagemode and a smooth transition and plunger force on the other when theplunger is transitioned to dispensing mode. This configuration is muchpreferred to a compressible ring carrier, since that would add a levelof complexity and difficulty (i.e., another variable) to achievingadequate seal and desirable plunger force.

Optionally, in any embodiment, the liquid sealing section is a separatecomponent and made of a different composition, from the ring carrier.For example, the ring carrier may be made from a polyolefin while theliquid sealing section may be a fluoropolymer-covered injection moldedTPE over a rigid polymeric skeleton. In such a case, the liquid sealingsection is more flexible (and resilient) compared to the rigid ringcarrier. In any embodiment of plungers according to the invention, theliquid sealing section may be more flexible and resilient than the rigidring carrier.

The inventors have learned that the manner in which the storage ring isinserted into a syringe barrel is consequential. For example, it hasbeen discovered that sliding the storage ring (e.g., using ashaft/sleeve) onto the storage platform once the plunger head has beeninserted into the syringe barrel may cause torsional and circumferentialdistortion of the storage ring and/or create an unwanted “pressure zone”between the storage ring and the liquid sealing section. Such a pressurezone, which traps pressurized air between the two sealing sections, mayhave the tendency to push the storage ring back over time and can resultin unwanted pressure against the liquid contents of a prefilled syringe.

To address these problems, the inventors have developed the alternativeembodiment of a convertible plunger 724 shown in FIGS. 21-23C. Theplunger 724 is, to some extent, structurally and functionally similar tothe plunger 324 of FIGS. 10-12, although there are important differencesto the construction and assembly of the plunger 724. Like itscounterpart in FIGS. 10-12, the convertible plunger 724 is configuredfor operating in a sealing mode (wherein the storage sealing section inan engagement position) and gliding mode (wherein the storage sealingsection is shifted to a release position), substantially as describedabove. Also, the convertible plunger 724 is of the independent storagesealing section plunger type. For the sake of brevity, similar featuresas between the two embodiments (e.g., material and configuration of thestorage ring, the manner in which the plunger is secured to a plungerrod, the basic function of the plunger, etc.) will not be discussed ingreat depth here. However, differences may be noted. The convertibleplunger comprises a ring carrier in the form of a rigid central core732, which would be coaxial with the central axis of a syringe barrelwhen assembled into a syringe (e.g., the syringe barrel 12 of FIG. 1).The storage sealing section 734, in the form of a storage ring 738, ismounted on a portion of the central core 732. The central core 732 is anelongated rigid member comprising, from the proximal end thereof, aflange 752 (which may be secured to a plunger rod, e.g., via threadedengagement or snap fit) which is adjacent to an annular dispensingplatform 748. Distal to the dispensing platform 748 is an annular steeptransition region 746 which leads to the annular storage platform 744.It has been found that the more steep or abrupt the transition region,the more smoothly the plunger transitions from storage mode todispensing mode. The outer diameter of the central core 732 narrowsdistally to the storage platform 744 to form two resilient prongs 772 ofan annular insertion platform 770, the function of which is describedbelow.

Unlike the embodiment of FIGS. 10-12, the central core 732 is mounted tothe proximal end of a connector body 780 (as opposed to the proximal endof a storage sealing section 336). The connector body 780 is apreferably rigid (e.g., polymeric) and generally cylindrical member, theproximal end of which receives and connects to the resilient prongs 772of the central core 732. The liquid sealing section 736 is mounted tothe distal end of the connector body 780 in essentially the same way asthe liquid sealing section 336 mounts to the central core 332 of FIGS.10-12. The description above with respect to the liquid sealing section336 will suffice for description of the same vis-à-vis the plunger 724of FIGS. 21-23C. It will only be briefly noted that the liquid sealingsection 736 optionally comprises a head 754 having a film 756 wrappedthereon. Notably, the film 756 is wrapped entirely around the head 754and continues along an underside of the head 754, wherein the film 756is sandwiched between the head 754 and the connector body 780. The head754 comprises a stem 763 that is assembled and secured into a centralmating recess 760 of the connector body 780, e.g., by ultrasonicwelding, an adhesive, a press-fit, a snap-fit or through threadedengagement.

The connector body 780 comprises an axial channel 784 leading to a wideropening 776 that optionally bores entirely through a center portion ofthe connector body 780, in a direction perpendicular to the central axisof the axial channel 784. This configuration simplifies injectionmolding of the connector body 780. The opening 776 comprises a ridgesection 782 adjacent to where the axial channel 784 meets the opening776. The prongs 772, at their distal ends, comprise radially outwardprojecting abutments 774. The abutments 774 are retained underneath theridge section 782 to secure the central core 732 to the connector body780.

To assemble the central core 732 to the connector body 780, the twocomponents should be aligned and axially centered. The prongs 772 of thecentral core 732 are then inserted into the axial channel 784 of theconnector body 780. The axial channel 784 is configured to facilitatethe insertion of the prongs 772, e.g., with an annular chamfer 786 atthe proximal end of the axial channel 784. When the prongs 772 contactthe chamfer 786, the prongs 772 are urged to resiliently flex orcompress radially inward so that the prongs 772 and abutments 774 fitentirely within the axial channel 784 as the prongs 772 are moveddistally into the axial channel 784. Once the abutments 774 fully reachthe wider opening 776, the prongs 772 are released from their compressedstate and the abutments 774 are retained underneath the ridge section782, preventing the central core 732 from being separated from theconnector body 780. In short, the prongs 772 secure the central core 732to the connector body 780 in a snap-fit configuration. This providesadvantages during assembly of the plunger 724 into a syringe barrel, asexplained now.

FIGS. 22A and 22B are schematic drawings illustrating the manner inwhich the storage ring 738 via the central core 732 are assembled ontothe connector body 780 and liquid sealing section 736 subassembly, thusforming a completed convertible plunger 724. FIG. 22A shows thecomponents just prior to fully assembling them to form the plunger 724.As shown, the distal end of the central core 732 is protruding slightlyinto the axial channel 784 of the connector body 780 and is thus not yetsecured thereto. Notably, in this position, the storage ring 738 isdisposed on the annular insertion platform 770 of the central core 732or ring carrier. The annular insertion platform 770 has a narrower outerdiameter than the annular storage platform 744. As such, the outerdiameter of the storage ring 738 is correspondingly less than the ring's738 outer diameter when disposed on the storage platform 744, as shownin FIG. 22B. The comparatively small outer diameter of the storage ring738, when disposed about the insertion platform 770, is configured tofacilitate insertion of the ring 738 into a syringe barrel in such a waythat the ring 738 does not contact the barrel wall or has only minimalcontact with it. When on the insertion platform 770, the sealing ring738 is in a “load position” wherein the ring 738 slides easily into theproximal end of the syringe barrel. As the prongs 772 are urged downwardinto the axial channel 784 of the connector body 780 to ultimatelysecure the central core 732 thereto (as shown in FIG. 22B), the storagering 738 transitions from load position on the insertion platform 770 toengagement position, wherein the ring is disposed about the storageplatform 744. Optionally, as shown in FIG. 22B, the entire ring 738,when the plunger is in storage mode, is disposed about the storageplatform 744. In other words, no part of the ring 738 contacts thedispensing platform when in storage mode. This helps facilitatestability of the storage ring 738. Likewise, as shown in FIG. 21, theentire ring 738 is optionally disposed about the dispensing platform 748when the plunger 724 is in dispensing mode, which facilitates stabilityduring dispensing.

Notably, with the aforementioned process, the ring 738 is not separatelyurged or pushed with a device to set the ring 738 into engagement mode.Rather, the ring 738 is inserted into the syringe barrel with little orno barrel sidewall resistance by placing the ring in load position onthe central core 732 before mounting the central core 732 to theconnector body 780. As seen in both FIGS. 22A and 22B, the ring 738 isflush against the proximal end of the connector body when the ring is inload position and in engagement position. In other words, the ring 738remains in a fixed position during loading while central core 732 movesrelative to the ring. With no space between the ring 738 and theconnector body 728 both before and after the ring 738 compresses againstthe barrel sidewall, there is no “pressure zone” between the storagering 738 and the liquid sealing section 736. This design, therefore,addresses the problems identified above with loading the storage ringwithout distorting it or creating an unwanted pressure zone.

The schematic drawings of FIGS. 23A-23C more fully illustrate the mannerin which the components of the convertible plunger 724 may be loadedinto a prefilled syringe and assembled. As shown in FIG. 23A, the liquidsealing section 736 and connector body 780 subassembly may be loadedinto the plunger via traditional methods to load plungers. These includevent tube, vacuum loading and vacuum assist, all of which are described,below. Next, the storage ring 738 and central core 732 subassembly iscreated by disposing the ring 738 in load position 738 on the prongs 772of the central core 732. As shown in FIG. 23C, the storage ring 738 andcentral core 732 subassembly is inserted, e.g., by push-rod or by aplunger rod assembled thereto, until the snap-fit is established withthe connector body 780 to form the fully assembled convertible plunger,loaded in engagement mode. It is contemplated that liquid prefilled inthe barrel provides resistance necessary to oppose the downward forceapplied when assembling the central core 732 to the connector body 780.The plunger 724 then may be used, just as described with otherembodiments, to convert the plunger 724 from engagement position (shownin FIG. 23C) to release position (shown in FIG. 21). It should be notedthat the expanded state of the plunger 724 is reducible to a constrictedstate by an operation that is applied to the internal portion of theplunger to reduce or eliminate the outward radial pressure provided by acomparatively rigid internal portion, in this case, the storage platform744 of the ring carrier 732. The ring 738 is set in the expanded statethrough application of a setting force onto the convertible plunger 724in a distal direction. The operation to reduce the plunger to theconstricted state comprises application of an actuation force onto theconvertible plunger 724 in the distal direction. With such a preferredembodiment, the plunger 724 does not need to be pulled back or primed toset it in, or remove it from engagement mode, before transitioning todispensing mode and then dispensing product.

FIG. 24 is an axial sectional view of an alternative convertible plungeridentical to the plunger of FIG. 21, except that the cross-section ofthe storage ring of FIG. 24 is an alternative geometry compared to thatof FIG. 21. FIG. 24A is an enlarged partial view of the plunger of FIG.24 highlighting the alternative geometry of the cross-section of thestorage ring. As shown, the alternative storage ring 738 i includes anouter surface facing generally radially outward away from the ringcarrier. In its uncompressed state, the ring 738 i includes a proximalend 738 p, a distal end 738 d and a radial plane of symmetry PS betweenthe proximal 738 p and distal 738 d ends. Optionally, radial plane ofsymmetry PS is equidistant from the proximal 738 p and distal 738 dends. The outer surface of the ring 738 i is symmetrical on either sideof the radial plane of symmetry PS. Optionally, the ring 738 i isconfigured such that, in its uncompressed state, a given rib on theinside surface opposes a rib on the outside surface of the storagesealing section 734 i. These features may help to facilitate stableseating and translation of the ring 738 i. Further, the distal end ofthe ring 738 b contacts the proximal end 785 of the connector body 780,without being disposed in or pressing against the annular chamfer 786.

Additional Methods and Apparatus for Assembling Convertible Plunger intoSyringe Barrel

Given the novel configuration of the convertible plunger, as representedby exemplary embodiments described herein, traditional methods forassembling a conventional plunger into a prefilled syringe barrel aftera filling operation, are not alone sufficient to assemble theconvertible plunger into a syringe barrel. Traditional methods, however,may be incorporated into aspects of novel methods for assembling theconvertible plunger into a syringe barrel.

There are three traditional methods for assembling a conventionalplunger into a prefilled syringe. The first is use of a vent tube,wherein the plunger is pushed through a tube that is placed into thesyringe and exits out the bottom of the tube into its final positionwithin the syringe barrel. The second is use of a vacuum, which iscreated in the syringe and the plunger is introduced into the openingthereof. Differential pressure forces the plunger down into the barrelinto a final position. A third method, known as vacuum assist, creates avacuum and further includes a mechanical element to assist the plungerinto its final position. Again, these traditional methods may be used tosome extent to effectuate assembly of a convertible plunger into thesyringe barrel. However, since the convertible plunger requires not onlythe plunger head to be disposed within the syringe barrel (which may bedone, e.g., via one of the traditional methods recited above), but alsosetting the storage sealing section into an engagement position,traditional methods/apparatus are not equipped to adequately assembleconvertible plungers into a medical barrel, such as a syringe. Thissection of the specification describes various methods and apparatus forassembling a convertible plunger into a syringe barrel. FIGS. 6A-6E,13-16B and 18 illustrate apparatus for assembling independent storagesealing section plunger type embodiments into a syringe barrel. FIGS.16A-17B illustrate apparatus for assembling insert and sleeve plungertype embodiments into a syringe barrel.

Independent storage sealing section plunger embodiments present theissue that the storage ring, if initially positioned in engagement mode(i.e., at its largest diameter), can render it difficult or impossibleto effectuate automated plunger insertion into a syringe barrel.Applicants have therefore determined that it is preferred that suchembodiments are not initially inserted into a syringe with the storagering in (expanded) engagement position, but instead in (constricted)release position. Once the plunger is initially inserted in the barrel,e.g., through a traditional method, the storage ring may be displacedfrom release position and set in engagement position for commercial use.

Turning now to FIGS. 6A to 6E the details of the assembly of thecomponents making up the plunger assembly 20 within the barrel 12 of thesyringe will now be described. To that end, the convertible plunger 24is provided in the state wherein its O-ring 38 is located immediatelyunder the flange 52. Thus the O-ring will be in its constricted state sothat it will not engage the interior surface of the barrel whenintroduced therein. With the convertible plunger 24 in that state it isintroduced into the proximal open end of the barrel 12 and freely slidto the longitudinal position it will be when in the plunger assembly isin its engagement position, like shown in FIG. 6A. A tubular tool 180whose inner diameter is slightly larger than the outer diameter of theflange 52 of the central core 32 is then slid over that portion of thecentral core to engage a portion of the O-ring 38 disposed thereunder,such as shown in FIG. 6B. The tool 180 is then pushed downward to causethe O-ring to slide along the central core in the distal direction,whereupon it will ride up over the conical section 46 and thus bestretched radially outward, like shown in FIG. 6C. Continued pressing onthe tool will eventually slide the O-ring into the annular recess 44,like shown in FIG. 6D whereupon it will snap into place in the holdingposition. Once that has been accomplished the tool 170 can be removedand the plunger rod 22 can then be connected to the convertible plunger24. To that end the threaded projection 26 at the distal end of theplunger rod 22 can be screwed into the threaded hole or bore 28 in thecentral core, thereby completing the assembly of the plunger assemblywithin the syringe's barrel.

Referring to FIG. 13, there is shown an optional embodiment of a plungerinsertion apparatus 1000, used, e.g., to set the convertible plunger 324of FIGS. 10-12 in a syringe barrel. As a first step in a method ofassembly, as discussed above, one of the traditional methods (e.g., venttube, vacuum or vacuum assist) may be employed to initially dispose theplunger 324 within a syringe barrel. The apparatus 1000 may be used in asecond step to set the ring 338 into engagement mode by displacing itfrom an initial position on the dispensing platform 348 to a position onthe storage platform 344 of the central core 332.

The apparatus 1000 includes a mount 1010 which initially drives theentire plunger 324 distally in direction D using the plunger positioningrod 1004 until flanged end 1006 of the positioning rod 1004 is blockedby stops 1012, at which point plunger movement ceases. The continueddownward movement collapses a spring 1008 affixed to a proximal end ofthe plunger positioning rod 1004, which causes an insertion tube 1002that is axially driven distally in direction D by the mount 1010continues to move distally to displace the storage ring 338 into theengagement position or storage sealing mode.

Referring to FIGS. 14A-C, there is shown an alternative optionalembodiment of a plunger insertion apparatus 1020, used, e.g., to set theconvertible plunger 324 of FIGS. 10-12 in a syringe barrel. As a firststep in a method of assembly, as discussed above, one of the traditionalmethods (e.g., vent tube, vacuum or vacuum assist) may be employed toinitially dispose the plunger 324 within a syringe barrel. The apparatus1020 may be used in a second step to set the ring 338 into engagementmode by displacing it from an initial position on the dispensingplatform 348 to a position on the storage platform 344 of the centralcore 332.

The apparatus 1020 includes a mount 1030 which actuates a tubularstructure (similar to a vent tube) that includes an inner and outercomponent. Namely, an insertion tube 1022 is configured to drive thestorage ring 338 distally in direction D while the outer constrictiontube 1023 initially surrounds and constrains the outer diameter of thering 338. Once the ring 338 is disposed about the storage platform 344of the central core 332, the tube structure retracts (see FIG. 14B) suchthat the constriction tube 1023 releases the ring 338, enabling the ring338 contact the barrel wall in the engagement position. The apparatus1020 further includes a spring 1028, stops 1032 and a plungerpositioning rod 1024 which function substantially as described abovewith respect to like components of the apparatus 1000 of FIG. 13. Themount 1030 initially drives the entire plunger 324 distally in directionD using the plunger positioning rod 1024 until the rim 1026 at theproximal end of the insertion tube 1022 is blocked by the stops 1032, atwhich point plunger movement ceases. However, the spring 1028 allows theconstriction tube 1023 to continue past that point. The constrictiontube 1023 first captures the outer diameter of the ring 338 and thenmoves down to the final position. The insertion tube 1022 movesindependently of the mount 1030 to allow for the insertion tube 1022 toengage the storage ring 338 to support it during the phase when theconstriction tube 1023 is capturing the sealing ring 338. The insertiontube 1022 remains in place to retain the sealing ring 338 in anengagement position while retracting the constriction tube 1023.

Referring to FIGS. 15A and 15B, there is shown an alternative optionalembodiment of a plunger insertion apparatus 1040, used, e.g., to set theconvertible plunger 324 of FIGS. 10-12 in a syringe barrel. As a firststep in a method of assembly, as discussed above, one of the traditionalmethods (e.g., vent tube, vacuum or vacuum assist) may be employed toinitially dispose the plunger 324 within a syringe barrel. The apparatus1040 may be used in a second step to set the ring 338 into engagementmode by displacing it from an initial position on the dispensingplatform 348 to a position on the storage platform 344 of the centralcore 332.

The outer diameter of the storage ring 338 is initially constrained bythe constriction portion 1043 of a removable tubular component 1042. Thecomponent 1042 may be placed in position when the plunger 324 ismanufactured or at the point of use before insertion into a syringe. Ifthe removable tubular component 1042 is placed in position when theplunger is manufactured, the component 1042 may be disposable. If theremovable tubular component 1042 is placed in position at the point ofuse, the component 1042 may be reusable. Once the storage ring 338 isplaced onto the storage platform 344, the removable tubular component1042 retracts and the storage ring 338 can expand into the engagementposition.

As with other embodiments discussed above, the apparatus 1040 includes amount 1050, spring 1048 and plunger positioning rod 1044. Optionally,the rod 1044 is telescoping to position the plunger 324 and engage theremovable tubular component 1042 to remove it. There is further an outerframe 1045 that passes through the removable tubular component 1042 toengage the storage ring 338. An independent motion retains the sealingring in a desired position while the removable tubular component 1042 isretracted.

Referring now to FIG. 18, there is shown an alternative embodiment of aconvertible plunger 624. The plunger 624, like the embodiment of FIGS.10-12, includes a film 656 on a plunger head 654 that is secured to aninternal rigid support 661. The plunger 624 also includes a central core632, but unlike other embodiments disclosed herein, the central core 632is not exposed to ambient conditions, such as moisture, oxygen orunsterile conditions. In this embodiment, the storage ring 638 coversthe proximal end of the central core 632 and also provides gas-tightsealing to protect syringe contents from the ambient environment. Thering 638 includes three ribs 638 a with valleys 638 b on either side ofthe middle rib 638 a. Such multi ribbed configuration is advantageousfor reasons provided above. An internal seal actuator 655 is positionedaround a proximal portion of the central core 632 and is surrounded, inpart, by the storage ring 638. The seal actuator 655 is configured toslide on the central core 632. The outer profile of the actuator 655includes two ramped sections (a,c) and a flat section (b) therebetween.

The internal actuator 655 may be assembled onto the central core 632 andthe material of the central core 632 may be displaced (e.g., viapeening, ultrasonic energy, melting, etc.) over to retain the actuator655. At that point, the storage ring 338 may be assembled onto thecentral core 632. The ramp (a) may retain the storage ring 338.

The plunger 624 may be inserted in a barrel initially by vacuum orvacuum assist. To set the ring 638 in engagement position, the ring 638is displaced distally, which in turn moves the internal seal actuator655 distally so that the flat section (b) compresses the ribs 638 aagainst the barrel wall. If vacuum assist is used as a method step inassembling the plunger, a telescoping element such as that shown in FIG.16A (discussed below) may be used to displace the ring 338 in the centerinitially to position the plunger 624 and then the larger diameter tubeto move the actuator 655 into position.

In use, the convertible plunger 624 may be actuated simply by pushing itdistally to dispense the syringe contents. The initial movementdisplaces the actuator 655 further to release the storage ring 638 fromengagement position and transition it to dispensing position. Continuedmovement displaces the plunger distally 624 down the barrel.

As mentioned above, methods and apparatus are also described in thisspecification for assembling insert and sleeve plunger type embodimentsinto a syringe barrel. One such apparatus is shown in FIGS. 16A and 16B.The insert and sleeve convertible plunger 424 includes a preferablyelastomeric plunger sleeve 423 having a storage sealing section 434 andliquid sealing section 436. The plunger sleeve 423 further comprisesinternal cavities 447, 448, 450, which are in communication with eachother and are configured to receive movable insertion of an insert 442.Cavity 448 is adjacent to the storage sealing section 434. When theplunger 424 is in engagement position, the insert 442 is disposed in thecavity 448 to provide compression of the storage sealing section 434against a syringe barrel wall. To transition to dispensing mode, theinsert 442 is advanced from cavity 448 to cavity 450.

The proximal most cavity or pre-load cavity 447 is the initial locationof the insert 442 when assembling the plunger 424 into a syringe barrel.In this position, the plunger does not provide gas-tight compressionagainst the syringe barrel, enabling the plunger 424 to advance distallyto a desired point within the syringe. Such insertion may be effectuatedwith the plunger insertion apparatus 1060. The apparatus includes amount 1070, spring 1068, central rod 1064, outer sleeve 1062, flangedend 1066 of the central rod 1064 and stops 1072. The rod 1064 may placethe plunger 424 in the proper location with a syringe. A collapsingsleeve 1062 continues to move distally after the plunger is positioned.The continued movement moves the insert 442 into cavity 448 where thestorage sealing section 434 becomes set in the engagement position forcommercial distribution.

Referring to FIGS. 17A and 17B, there is shown a plunger insertionapparatus 1080 for an insert and sleeve convertible plunger 524. Theplunger 524 includes a preferably elastomeric plunger sleeve 523 havinga storage sealing section 534 and liquid sealing section 536. Theplunger sleeve 523 further comprises internal cavities 547, 548 and 550,which are in communication with each other and are configured to receivemovable insertion of an insert 542. Cavity 548 is adjacent to thestorage sealing section 534. When the plunger 524 is in engagementposition, the insert 542 is disposed in the cavity 548 to providecompression of the storage sealing section 534 against a syringe barrelwall. To transition to dispensing mode, the insert 542 is advanced fromcavity 548 to cavity 550.

When initially disposing the plunger 524 within a syringe barrel, theinsert 542 is initially positioned in the distal most cavity, 550. Inthis position, the insert may be advanced in the barrel with the plungerpositioning rod 1084 that is disposed with a sleeve 1082 of theapparatus. A gripper 1083 is then used to grasp the proximal end of theinsert and retract the insert so that it is positioned within cavity548, thus generating compression of the storage sealing section 534against the syringe barrel to put the plunger 524 in an engagementposition.

Optionally in any embodiment of convertible plunger according to theinvention, the plunger provides a break loose force and glide forcebelow 15 N, optionally below 10 N, optionally below 9 N, optionallybelow 8 N. optionally below 7 N, optionally below 6 N, optionallybetween about 2.5 N and about 5.5 N, substantially or entirely withoutthe presence of a flowable lubricant between the barrel and theplunger's barrel-contacting surfaces. Optionally in any embodiment ofconvertible plunger according to the invention, the plunger provides adifferential between break loose force and glide force of optionallybelow 2 N, optionally below 1.5 N, optionally below 1.0 N, optionallybelow 0.5 N, optionally below 0.4 N, optionally below 0.25 N. Optionallyin any embodiment of convertible plunger according to the invention, theplunger provides a differential between break loose force and glideforce of optionally below 20%, optionally below 15%, optionally below12%, optionally below 10%, optionally below 8%, optionally between 2.5%and 6%. These differentials between break loose force and glide forceare provided substantially or entirely without the presence of aflowable lubricant between the barrel and the plunger'sbarrel-contacting surfaces.

In any embodiment, the liquid sealing section (via the plunger head)provides a liquid tight seal and optionally (albeit preferably) CCI. Ifa CCI level seal for the liquid sealing section is to be provided, thesterile barrier provided by the liquid sealing section may be verifiedby using both of the following two tests: (1) microbial ingress testingusing a liquid immersion technique; and (2) the dye penetration test.The microbial ingress test using a liquid immersion technique involvesproviding a challenge organism provided in a liquid, immersing thesample container in the liquid while a vacuum is applied to the contentssection of the container, and after a designated time, testing to see ifthe challenge organism migrated past the liquid sealing section. The dyepenetration test involves placing a sample container, with the plungerhead disposed therein, into a dye bath, applying a vacuum to obtain amanometer reading lower than 635 mmHg for two minutes and visually orusing an ultraviolet reading technique, determining whether any of thedye passed through the liquid sealing section. Ultimately, both testsshould be passed in order to verify CCI provided by the liquid sealingsection.

Absence of Flowable Lubricant in Injectable Drug Product

It has been observed that protein-based drugs can denature or otherwisedegrade. A principal way the drug denatures is to unfold and then tocause aggregates to form in the drug product. The primary container cancause protein to denature. One factor that can cause such denaturing isthe presence of silicone oil lubricant (a type of flowable lubricant).Droplets of silicone oil can detach from the container wall and interactwith the drug. These droplets cause proteins in the liquid to unfold.

A big problem with biologic drugs is the possibility of an immuneresponse by the patient. An immune response can be caused by aggregates(particles) in the drug that are injected into the patient. Theseaggregates may cause the production of antibodies in the patient that:(1) render the drug ineffective or (2) cause a severe autoimmuneresponse. A small quantity of particles can cause an immune response.The % of proteins that have aggregated in the drug may be very, verysmall but can cause an immune response. For example, drugs taken by MSand Crohn's Disease patients develop an immune response within 2 years.This requires the patient to stop taking the drug and/or switch drugs.

The number of protein-based drugs has increased significantly over thepast five years and this trend will continue. Drug therapies are beingused to treat more chronic indications. This means that patients aretaking the drugs longer and are more prone to side effects caused by thedrug. Previously, protein drugs were taken for acute indications andside effects were limited.

The amount of contaminants in the drug may increase over the shelf life.The threshold for measuring contaminants is at the detection limit ofthe instrumentation—so the concentrations are going lower and lower. Theconcentration of these particles is low ppb/ml, but this may still beenough to cause an immune response. Accordingly, the need to avoid useof flowable lubricants is particularly pressing with biologic drugs,i.e., polypeptide compositions or protein compositions that are providedin prefilled syringes.

In an optional aspect of the invention, a convertible plunger accordingto any embodiment disclosed herein, which does not require the use of aflowable lubricant between the syringe barrel wall and thebarrel-contacting surfaces of the plunger, is particularly beneficialfor prefilled syringes containing a polypeptide composition or proteincomposition. In this way, flowable lubricant, e.g., silicone oil, willnot migrate into the drug (and ultimately into the patient) andtherefore will not denature the biologic components of the drugcomposition. As such, shelf life of the biologic drug may be optimized.Moreover, in this way, undesired immune responses by the patientotherwise caused by silicone oil giving rise to aggregates in the drugcan be avoided. Thus an “oil-free solution” is particularly desirablefor biologics.

Accordingly, in an optional embodiment, the invention is directed to useof a convertible plunger according to any embodiment disclosed herein,disposed in a prefilled syringe. The syringe includes a medical barrelhaving an inner wall and an injectable drug product, optionally a liquidcomposition, disposed in a product containing area of the medicalbarrel, the injectable drug product comprising a polypeptide compositionor protein composition that is susceptible to denaturing frominteraction with particles generated from a flowable lubricant. Themedical barrel has a distal dispensing end for dispensing the injectabledrug product and an open proximal end configured for receipt of theconvertible plunger. According to an optional embodiment of theinvention, the polypeptide composition or protein composition issusceptible to one or more of the following negative effects frominteraction with particles generated from a flowable lubricant:denaturing of proteins in the composition; agglomeration of proteins inthe composition; degradation of proteins in the composition; triggeringan undesired immune response in a patient; and degrading efficacy of thedrug product. Flowable lubricant-generated particles are absent from thedrug product such that the drug product is not subject to any of theaforementioned negative effects that may otherwise result frominteraction with flowable lubricant-generated particles.

The present embodiments are particularly useful for the administrationof lyophilized pharmaceuticals, including small molecules andbiologicals, such as those presently marketed as lyophilized or powdereddrugs for injection. These include, by way of non-limiting examples,ActHIB® vaccine, Aldesleukin, ampicillin, asparaginase, amphotericin B(Amphotec, Amphocin, others), ATryn antithrombin, Bendamustine,Bleomycin, Bortezomib, Carboplatin, Carmustine, Caverject Powder(Alprostadil), Certolizumab (CIMZIA®), Cefazolin, Cefonicid,Ceftazidime, Ceftriaxone sodium, Cisplatin, Cytarabine, Cytoxan(cyclophosphamide), Dacarbazine, Daunorubicin, Degarelix,Desferrioxamine Mesilate, Doxorubicin (Adriamycin), Epirubicin,Erythrocin lactobionate, estrogen, Gemcitabine, glucagon, humanchorionic gonadotropin, human growth hormone, human menopausalgonadotropin (HMG, menotrpin), human plasma, HcG 5000 IU-5 ml, immuneglobulin (Carimune, Gammagard®), Interferon beta la (Avonex), Intron A(interferon alfa-2b), Kogenate FS (recombinant factor VII) Leucovorincalcium, leuproreline, methylprednisolone, Leukine (sargramostim),Menomune® vaccine, MMR and MMRV vaccines, Peginterferon alfa-2b(Peglntron), Remicade® infliximab, Sermorelin/GHRH6-5 ml, somatropin(Genotropin, Saizen®), Sincalide (Kinevac), thiotepa, Vecuroniumbromide, Vfend (voriconazole), Vincristine, Varicella vaccines, andZostavax.

Some excipients are included in powdered or lyophilized products, suchas solubilizers or buffers, may be considered functional excipients.Excipients used in various lyophilized formulations include bulkingagents, buffering agents, tonicity modifiers, antimicrobial agents,surfactants and co-solvents, and are well-known in the art. See, e.g.,Baheti et al., Excipients Used in Lyophilization of Small Molecules, 1J. Excipients & Food Chem. 41 (2010). Similarly, diluents are well-knownin the art, such as water for injection, and often include excipients,e.g., saline or Ringer's solution.

Industry Standards for Testing Aspects of Plunger

Testing of compression setting properties of the plunger assembly may beconducted using methods known in the art, for example, ASTM D395.

Testing of adhesive properties or bonding strength between the film andthe plunger may be conducted using methods known in the art, forexample, according to ASTM D1995-92(2011) or D1876-08.

Plunger sliding force is the force required to maintain movement of aplunger in a syringe or cartridge barrel, for example during aspirationor dispense. It can advantageously be determined using, e.g., the ISO7886-1:1993 test known in the art, or to the currently pending publishedtest method to be incorporated into ISO 11040-4. Plunger breakout force,which may be tested using the same method as that for testing plungersliding force, is the force required to start a stationary plungermoving within a syringe or cartridge barrel. Machinery useful in testingplunger sliding and breakout force is, e.g., an Instron machine using a50 N transducer.

Testing for extractables, i.e., amount of material that migrates fromthe plunger into the liquid within the syringe or cartridge, may beconducted using methods set forth in Ph. Eur. 2.9.17 Test forExtractable Volume of Parenteral Preparations, for example.

Testing of container closure integrity (CCI) may be done using a vacuumdecay leak detection method, wherein a vacuum his maintained inside of atest volume and pressure rise is measured over time. A large enoughpressure rise is an indication that there is flow into the system, whichis evidence of a leak. Optionally, the vacuum decay test is implementedover two separate cycles. The first cycle is dedicated to detectinglarge leaks over a very short duration. A relatively weak vacuum ispulled for the first cycle because if a gross leak is detected, a largepressure differential is not necessary to detect a large pressure rise.Use of a first cycle as described helps to shorten total test time if agross leak exists. If no leak is detected in the first cycle, a secondcycle is run, which complies with ASTM F2338-09 Standard Test Method forNondestructive Detection of Leaks in Packages by Vacuum Decay Method.The second cycle starts out with a system evaluation to lower the signalto noise ratio in the pressure rise measurements. A relatively strongvacuum is pulled for a long period of time in the second cycle toincrease the chance of detecting a pressure rise in the system.

Testing of air leakage past the syringe piston during aspiration may beconducted using methods known in the art, for example, ISO 7886-1:1993.

Testing of liquid leakage at syringe piston under compression may beconducted using methods known in the art, for example, ISO 7886-1:1993.

Convertible Plungers Used in PECVD-Coated Syringe Barrels

In another aspect, the present invention includes use of any embodiments(or combination of embodiments) of plungers according to the inventionin syringes having a PECVD coating or PECVD coating set. The syringesmay be made from, e.g., glass or plastic. Optionally, the syringe barrelaccording to any embodiment is made from an injection moldablethermoplastic material that appears clear and glass-like in final form,e.g., a cyclic olefin polymer (COP), cyclic olefin copolymer (COC) orpolycarbonate. Such materials may be manufactured, e.g., by injectionmolding, to very tight and precise tolerances (generally much tighterthan achievable with glass). This is a benefit when trying to balancethe competing considerations of seal tightness and low plunger force inplunger design.

This section of the disclosure focuses primarily on prefilled syringesas a preferred implementation of optional aspects of the invention.Again, however, it should be understood that the present invention mayinclude any parenteral container that utilizes a plunger, such assyringes, cartridges, auto-injectors, prefilled syringes, prefilledcartridges or vials.

For some applications, it may be desired to provide one or more coatingsor layers to the interior wall of a parenteral container to modify theproperties of that container. For example, one or more coatings orlayers may be added to a parenteral container, e.g., to improve thebarrier properties of the container and prevent interaction between thecontainer wall (or an underlying coating) and drug product held withinthe container. Such coatings or layers may be constructed in accordancewith the teachings of co-pending PCT Application PCT/US2014/023813,filed on Mar. 11, 2014, which is incorporated by reference herein in itsentirety.

For example, as shown in FIG. 1A, which is a first alternativeembodiment of an enlarged sectional view of the barrel 12 of the syringe10 of FIG. 1, the inner surface 14 of the barrel 12 may include acoating set 400 comprising one or more coatings or layers. The barrel 12may include at least one tie coating or layer 402, at least one barriercoating or layer 404, and at least one organo-siloxane coating or layer406. The organo-siloxane coating or layer 406 preferably has pHprotective properties. This embodiment of the coating set 400 isreferred to herein as a “tri-layer coating set” in which the the barriercoating or layer 404 of SiO_(x) is protected against contents having apH otherwise high enough to remove it by being sandwiched between the pHprotective organo-siloxane coating or layer 406 and the tie coating orlayer 402. The contemplated thicknesses of the respective layers innanometers (preferred ranges in parentheses) are given in the followingTri-layer Thickness Table:

Tri-layer Thickness Table Adhesion (nm) Barrier (nm) Protection (nm) 5-100 20-200  50-500 (5-20) (20-30)  (100-200)

Properties and compositions of each of the coatings that make up thetri-layer coating set are now described.

The tie coating or layer 402 has at least two functions. One function ofthe tie coating or layer 402 is to improve adhesion of a barrier coatingor layer 404 to a substrate (e.g., the inner surface 14 of the barrel12), in particular a thermoplastic substrate, although a tie layer canbe used to improve adhesion to a glass substrate or to another coatingor layer. For example, a tie coating or layer, also referred to as anadhesion layer or coating can be applied to the substrate and thebarrier layer can be applied to the adhesion layer to improve adhesionof the barrier layer or coating to the substrate.

Another function of the tie coating or layer 402 has been discovered: atie coating or layer 402 applied under a barrier coating or layer 404can improve the function of a pH protective organo-siloxane coating orlayer 406 applied over the barrier coating or layer 404.

The tie coating or layer 402 can be composed of, comprise, or consistessentially of SiO_(x)C_(y), in which x is between 0.5 and 2.4 and y isbetween 0.6 and 3. Alternatively, the atomic ratio can be expressed asthe formula Si_(w)O_(x)C_(y). The atomic ratios of Si, O, and C in thetie coating or layer 402 are, as several options:

-   -   Si 100: O 50-150: C 90-200 (i.e. w=1, x=0.5 to 1.5, y=0.9 to 2);    -   Si 100: O 70-130: C 90-200 (i.e. w=1, x=0.7 to 1.3, y=0.9 to 2)    -   Si 100: O 80-120: C 90-150 (i.e. w=1, x=0.8 to 1.2, y=0.9 to        1.5)    -   Si 100: O 90-120: C 90-140 (i.e. w=1, x=0.9 to 1.2, y=0.9 to        1.4), or    -   Si 100: O 92-107: C 116-133 (i.e. w=1, x=0.92 to 1.07, y=1.16 to        1.33).

The atomic ratio can be determined by XPS. Taking into account the Hatoms, which are not measured by XPS, the tie coating or layer 402 maythus in one aspect have the formula Si_(w)O_(x)C_(y)H_(z) (or itsequivalent S_(i)O_(x)C_(y)), for example where w is 1, x is from about0.5 to about 2.4, y is from about 0.6 to about 3, and z is from about 2to about 9. Typically, a tie coating or layer 402 would hence contain36% to 41% carbon normalized to 100% carbon plus oxygen plus silicon.

The barrier coating or layer 404 for any embodiment defined in thisspecification (unless otherwise specified in a particular instance) is acoating or layer, optionally applied by PECVD as indicated in U.S. Pat.No. 7,985,188. The barrier coating preferably is characterized as a“SiO_(x)” coating, and contains silicon, oxygen, and optionally otherelements, in which x, the ratio of oxygen to silicon atoms, is fromabout 1.5 to about 2.9. The thickness of the SiO_(x) or other barriercoating or layer can be measured, for example, by transmission electronmicroscopy (TEM), and its composition can be measured by X-rayphotoelectron spectroscopy (XPS). The barrier layer is effective toprevent oxygen, carbon dioxide, or other gases from entering thecontainer and/or to prevent leaching of the pharmaceutical material intoor through the container wall.

Preferred methods of applying the barrier 404 layer and tie layer 402 tothe inner surface 14 of the barrel 12 is by plasma enhanced chemicalvapor deposition (PECVD), such as described in, e.g., U.S. Pat. App.Pub. No. 20130291632, which is incorporated by reference herein in itsentirety.

The Applicant has found that barrier layers or coatings of SiO_(x) areeroded or dissolved by some fluids, for example aqueous compositionshaving a pH above about 5. Since coatings applied by chemical vapordeposition can be very thin—tens to hundreds of nanometers thick—even arelatively slow rate of erosion can remove or reduce the effectivenessof the barrier layer in less time than the desired shelf life of aproduct package. This is particularly a problem for fluid pharmaceuticalcompositions, since many of them have a pH of roughly 7, or more broadlyin the range of 5 to 9, similar to the pH of blood and other human oranimal fluids. The higher the pH of the pharmaceutical preparation, themore quickly it erodes or dissolves the SiO_(x) coating. Optionally,this problem can be addressed by protecting the barrier coating orlayer, or other pH sensitive material, with a pH protectiveorgano-siloxane coating or layer.

Optionally, the pH protective organo-siloxane coating or layer 406 canbe composed of, comprise, or consist essentially ofSi_(w)O_(x)C_(y)H_(z) (or its equivalent SiO_(x)C_(y)) orSi_(w)N_(x)C_(y)H_(z) or its equivalent SiN_(x)C_(y)). The atomic ratioof Si:O:C or Si:N:C can be determined by XPS (X-ray photoelectronspectroscopy). Taking into account the H atoms, the pH protectivecoating or layer may thus in one aspect have the formulaSi_(w)O_(x)C_(y)H_(z), or its equivalent SiO_(x)C_(y), for example wherew is 1, x is from about 0.5 to about 2.4, y is from about 0.6 to about3, and z is from about 2 to about 9.

Typically, expressed as the formula Si_(w)O_(x)C_(y), the atomic ratiosof Si, O, and C are, as several options:

-   -   Si 100: O 50-150: C 90-200 (i.e. w=1, x=0.5 to 1.5, y=0.9 to 2);    -   Si 100: O 70-130: C 90-200 (i.e. w=1, x=0.7 to 1.3, y=0.9 to 2)    -   Si 100: O 80-120: C 90-150 (i.e. w=1, x=0.8 to 1.2, y=0.9 to        1.5)    -   Si 100: O 90-120: C 90-140 (i.e. w=1, x=0.9 to 1.2, y=0.9 to        1.4)    -   Si 100: O 92-107: C 116-133 (i.e. w=1, x=0.92 to 1.07, y=1.16 to        1.33), or    -   Si 100: O 80-130: C 90-150.

Alternatively, the organo-siloxane coating or layer can have atomicconcentrations normalized to 100% carbon, oxygen, and silicon, asdetermined by X-ray photoelectron spectroscopy (XPS) of less than 50%carbon and more than 25% silicon. Alternatively, the atomicconcentrations are from 25 to 45% carbon, 25 to 65% silicon, and 10 to35% oxygen. Alternatively, the atomic concentrations are from 30 to 40%carbon, 32 to 52% silicon, and 20 to 27% oxygen. Alternatively, theatomic concentrations are from 33 to 37% carbon, 37 to 47% silicon, and22 to 26% oxygen.

Optionally, the atomic concentration of carbon in the pH protectivecoating or layer 406, normalized to 100% of carbon, oxygen, and silicon,as determined by X-ray photoelectron spectroscopy (XPS), can be greaterthan the atomic concentration of carbon in the atomic formula for theorganosilicon precursor. For example, embodiments are contemplated inwhich the atomic concentration of carbon increases by from 1 to 80atomic percent, alternatively from 10 to 70 atomic percent,alternatively from 20 to 60 atomic percent, alternatively from 30 to 50atomic percent, alternatively from 35 to 45 atomic percent,alternatively from 37 to 41 atomic percent.

Optionally, the atomic ratio of carbon to oxygen in the pH protectivecoating or layer 406 can be increased in comparison to the organosiliconprecursor, and/or the atomic ratio of oxygen to silicon can be decreasedin comparison to the organosilicon precursor.

An exemplary empirical composition for a pH protective coating accordingto the present invention is SiO_(1.3)C_(0.5)H_(3.6).

Optionally in any embodiment, the pH protective coating or layer 406comprises, consists essentially of, or consists of PECVD applied siliconcarbide.

Optionally in any embodiment, the pH protective coating or layer 406 isapplied by employing a precursor comprising, consisting essentially of,or consisting of a silane. Optionally in any embodiment, the silaneprecursor comprises, consists essentially of, or consists of any one ormore of an acyclic or cyclic silane, optionally comprising, consistingessentially of, or consisting of any one or more of silane,trimethylsilane, tetramethylsilane, Si2-Si4 silanes, triethyl silane,tetraethyl silane, tetrapropylsilane, tetrabutylsilane, oroctamethylcyclotetrasilane, or tetramethylcyclotetrasilane.

Optionally in any embodiment, the pH protective coating or layer 406comprises, consists essentially of, or consists of PECVD appliedamorphous or diamond-like carbon. Optionally in any embodiment, theamorphous or diamond-like carbon is applied using a hydrocarbonprecursor. Optionally in any embodiment, the hydrocarbon precursorcomprises, consists essentially of, or consists of a linear, branched,or cyclic alkane, alkene, alkadiene, or alkyne that is saturated orunsaturated, for example acetylene, methane, ethane, ethylene, propane,propylene, n-butane, i-butane, butane, propyne, butyne, cyclopropane,cyclobutane, cyclohexane, cyclohexene, cyclopentadiene, or a combinationof two or more of these. Optionally in any embodiment, the amorphous ordiamond-like carbon coating has a hydrogen atomic percent of from 0.1%to 40%, alternatively from 0.5% to 10%, alternatively from 1% to 2%,alternatively from 1.1 to 1.8%.

Optionally in any embodiment, the pH protective coating or layer 406comprises, consists essentially of, or consists of PECVD applied SiNb.Optionally in any embodiment, the PECVD applied SiNb is applied using asilane and a nitrogen-containing compound as precursors. Optionally inany embodiment, the silane is an acyclic or cyclic silane, optionallycomprising, consisting essentially of, or consisting of silane,trimethylsilane, tetramethylsilane, Si2-Si4 silanes, triethylsilane,tetraethylsilane, tetrapropylsilane, tetrabutylsilane,octamethylcyclotetrasilane, or a combination of two or more of these.Optionally in any embodiment, the nitrogen-containing compoundcomprises, consists essentially of, or consists of any one or more of:nitrogen gas, nitrous oxide, ammonia or a silazane. Optionally in anyembodiment, the silazane comprises, consists essentially of, or consistsof a linear silazane, for example hexamethylene disilazane (HMDZ), amonocyclic silazane, a polycyclic silazane, a polysilsesquiazane, or acombination of two or more of these.

Optionally in any embodiment, the PECVD for the pH protective coating orlayer 406 is carried out in the substantial absence or complete absenceof an oxidizing gas. Optionally in any embodiment, the PECVD for the pHprotective coating or layer 406 is carried out in the substantialabsence or complete absence of a carrier gas.

Optionally an FTIR absorbance spectrum of the pH protective coating orlayer 406 SiOxCyHz has a ratio greater than 0.75 between the maximumamplitude of the Si—O—Si symmetrical stretch peak normally locatedbetween about 1000 and 1040 cm-1, and the maximum amplitude of theSi—O—Si asymmetric stretch peak normally located between about 1060 andabout 1100 cm-1. Alternatively in any embodiment, this ratio can be atleast 0.8, or at least 0.9, or at least 1.0, or at least 1.1, or atleast 1.2. Alternatively in any embodiment, this ratio can be at most1.7, or at most 1.6, or at most 1.5, or at most 1.4, or at most 1.3. Anyminimum ratio stated here can be combined with any maximum ratio statedhere, as an alternative embodiment.

Optionally, in any embodiment the pH protective coating or layer 406, inthe absence of the medicament, has a non-oily appearance. Thisappearance has been observed in some instances to distinguish aneffective pH protective coating or layer 406 from a lubricity layer(e.g., as described in U.S. Pat. No. 7,985,188), which in some instanceshas been observed to have an oily (i.e. shiny) appearance.

The pH protective coating or layer optionally can be applied by plasmaenhanced chemical vapor deposition (PECVD) of a precursor feedcomprising an acyclic siloxane, a monocyclic siloxane, a polycyclicsiloxane, a polysilsesquioxane, a monocyclic silazane, a polycyclicsilazane, a polysilsesquiazane, a silatrane, a silquasilatrane, asilproatrane, an azasilatrane, an azasilquasiatrane, an azasilproatrane,or a combination of any two or more of these precursors. Someparticular, non-limiting precursors contemplated for such use includeoctamethylcyclotetrasiloxane (OMCTS).

Optionally, an FTIR absorbance spectrum of the pH protective coating orlayer 406 of composition SiOxCyHz has a ratio greater than 0.75 betweenthe maximum amplitude of the Si—O—Si symmetrical stretch peak betweenabout 1000 and 1040 cm-1, and the maximum amplitude of the Si—O—Siasymmetric stretch peak between about 1060 and about 1100 cm-1.

Other precursors and methods can be used to apply the pH protectivecoating or layer 406 or passivating treatment. For example,hexamethylene disilazane (HMDZ) can be used as the precursor. HMDZ hasthe advantage of containing no oxygen in its molecular structure. Thispassivation treatment is contemplated to be a surface treatment of theSiOx barrier layer with HMDZ. To slow down and/or eliminate thedecomposition of the silicon dioxide coatings at silanol bonding sites,the coating must be passivated. It is contemplated that passivation ofthe surface with HMDZ (and optionally application of a few mono layersof the HMDZ-derived coating) will result in a toughening of the surfaceagainst dissolution, resulting in reduced decomposition. It iscontemplated that HMDZ will react with the —OH sites that are present inthe silicon dioxide coating, resulting in the evolution of NH3 andbonding of S—(CH3)3 to the silicon (it is contemplated that hydrogenatoms will be evolved and bond with nitrogen from the HMDZ to produceNH3).

Another way of applying the pH protective coating or layer is to applyas the pH protective coating or layer an amorphous carbon orfluorocarbon coating, or a combination of the two.

Amorphous carbon coatings can be formed by PECVD using a saturatedhydrocarbon, (e.g. methane or propane) or an unsaturated hydrocarbon(e.g. ethylene, acetylene) as a precursor for plasma polymerization.Fluorocarbon coatings can be derived from fluorocarbons (for example,hexafluoroethylene or tetrafluoroethylene). Either type of coating, or acombination of both, can be deposited by vacuum PECVD or atmosphericpressure PECVD. It is contemplated that that an amorphous carbon and/orfluorocarbon coating will provide better passivation of an SiOx barrierlayer than a siloxane coating since an amorphous carbon and/orfluorocarbon coating will not contain silanol bonds.

It is further contemplated that fluorosilicon precursors can be used toprovide a pH protective coating or layer over a SiOx barrier layer. Thiscan be carried out by using as a precursor a fluorinated silaneprecursor such as hexafluorosilane and a PECVD process. The resultingcoating would also be expected to be a non-wetting coating.

Yet another coating modality contemplated for protecting or passivatinga SiOx barrier layer is coating the barrier layer using a polyamidoamineepichlorohydrin resin. For example, the barrier coated part can be dipcoated in a fluid polyamidoamine epichlorohydrin resin melt, solution ordispersion and cured by autoclaving or other heating at a temperaturebetween 60 and 100° C. It is contemplated that a coating ofpolyamidoamine epichlorohydrin resin can be preferentially used inaqueous environments between pH 5-8, as such resins are known to providehigh wet strength in paper in that pH range. Wet strength is the abilityto maintain mechanical strength of paper subjected to complete watersoaking for extended periods of time, so it is contemplated that acoating of polyamidoamine epichlorohydrin resin on a SiOx barrier layerwill have similar resistance to dissolution in aqueous media. It is alsocontemplated that, because polyamidoamine epichlorohydrin resin impartsa lubricity improvement to paper, it will also provide lubricity in theform of a coating on a thermoplastic surface made of, for example, COCor COP.

Even another approach for protecting a SiOx layer is to apply as a pHprotective coating or layer a liquid-applied coating of apolyfluoroalkyl ether, followed by atmospheric plasma curing the pHprotective coating or layer. For example, it is contemplated that theprocess practiced under the trademark TriboGlide® can be used to providea pH protective coating or layer 406 that is also provides lubricity.

Thus, a pH protective coating for a thermoplastic syringe wall accordingto an aspect of the invention may comprise, consist essentially of, orconsist of any one of the following: plasma enhanced chemical vapordeposition (PECVD) applied silicon carbide having the formula SiOxCyHz,in which x is from 0 to 0.5, alternatively from 0 to 0.49, alternativelyfrom 0 to 0.25 as measured by X ray photoelectron spectroscopy (XPS), yis from about 0.5 to about 1.5, alternatively from about 0.8 to about1.2, alternatively about 1, as measured by XPS, and z is from 0 to 2 asmeasured by Rutherford Backscattering Spectrometry (RBS), alternativelyby Hydrogen Forward Scattering Spectrometry (HFS); or PECVD appliedamorphous or diamond-like carbon, CHz, in which z is from 0 to 0.7,alternatively from 0.005 to 0.1, alternatively from 0.01 to 0.02; orPECVD applied SiNb, in which b is from about 0.5 to about 2.1,alternatively from about 0.9 to about 1.6, alternatively from about 1.2to about 1.4, as measured by XPS.

PECVD apparatus suitable for applying any of the PECVD coatings orlayers described in this specification, including the tie coating orlayer, the barrier coating or layer or the organo-siloxane coating orlayer, is shown and described in U.S. Pat. No. 7,985,188 and U.S. Pat.App. Pub. No. 20130291632. This apparatus optionally includes a vesselholder, an inner electrode, an outer electrode, and a power supply. Avessel seated on the vessel holder defines a plasma reaction chamber,optionally serving as its own vacuum chamber. Optionally, a source ofvacuum, a reactant gas source, a gas feed or a combination of two ormore of these can be supplied. Optionally, a gas drain, not necessarilyincluding a source of vacuum, is provided to transfer gas to or from theinterior of a vessel seated on the port to define a closed chamber.

It is contemplated that syringes having a plunger-contacting innersurface comprising an organo-siloxane coating, without a separatediscrete lubricity coating or substantially without the presence of aflowable lubricant, may still provide adequate lubricity for plungeradvancement. As used herein, “substantially without the presence of aflowable lubricant,” means that a flowable lubricant (e.g., PDMS) is notprovided to a syringe barrel in amounts that would contribute to thelubricity of the plunger-syringe system. Since it is sometimes thepractice to use a flowable lubricant when handling plungers prior toassembling them into syringes, “substantially without the presence of aflowable lubricant” in some cases may contemplate the presence of traceamounts of such lubricant as a result of such handling practices.

Accordingly, in one aspect, the invention is directed to anorgano-siloxane coating on the inner surface of a parenteral containerwhich provides lubricious properties conducive to acceptable plungeroperation. The organo-siloxane coating may, for example, be anyembodiment of the pH protective coating discussed above. Theorgano-siloxane coating may be applied directly to the interior wall ofthe container or as a top layer on a multi-layer coating set, e.g., thetri-layer coating set discussed above. Preferably, this embodiment wouldobviate the need for a discrete lubricity coating, e.g., as described inU.S. Pat. No. 7,985,188 or a flowable lubricant, e.g., silicone oil.

The organo-siloxane coating can optionally provide multiple functions:(1) a pH resistant layer that protects an underlying layer or underlyingpolymer substrate from drug products having a pH from 4-10, optionallyfrom 5-9; (2) a drug contact surface that minimizes aggregation,extractables and leaching; (3) in the case of a protein-based drug,reduced protein binding on the container surface; and (4) a lubricatinglayer, e.g., to facilitate plunger advancement when dispensing contentsof a syringe.

Use of an organo-siloxane coating on a polymer-based container as thecontact surface for a plunger provides distinct advantages. Plasticsyringes and cartridges may be injection molded to tighter tolerancesthan their glass counterparts. It is contemplated that the dimensionalprecision achievable through injection molding allows optimization ofthe inside diameter of a syringe to provide sufficient compression tothe plunger for CCI and gas-tightness on the one hand, while notover-compressing the plunger so as to provide desired plunger force uponadministration of the drug product. Optimally, this would eliminate ordramatically reduce the need for lubricating the syringe or cartridgewith a flowable lubricant or a discrete lubricity coating, thus reducingmanufacturing complexity and avoiding problems associated with siliconeoil.

Various aspects of the invention will be illustrated in more detail withreference to the following Examples, but it should be understood thatthe present invention is not deemed to be limited thereto.

EXAMPLES Example 1: Low and Consistent F_(i) and F_(m)

In this example, it is demonstrated how convertible plungers accordingto an aspect of the present invention achieved extraordinarily low andconsistent breakout force F_(i) and maintenance force F_(m) with only avery slight difference in average F_(i) versus F_(m). Most notably,these forces were achieved without the presence of flowable lubricantbetween the syringe barrel and barrel-contacting surfaces of theplunger. These results are especially surprising since the plungerprovides robust CCI and gas-tight sealing configured to protect thesterility and quality of contents within the syringe over a typicalshelf-life of a prefilled syringe (see Example 2, below).

A group of eighteen plungers having the configuration of the convertibleplunger 324 of FIGS. 10-12 were assembled and set into storage sealingmode within plastic syringes having tri-layer coating sets 400 (FIG. 1A)deposited on the inner surfaces thereof. The syringes were filled withwater for injection. Each of the plungers were actuated to transitionfrom storage sealing mode to dispensing mode and then were advanceddistally down each syringe barrel to dispense the water.

FIGS. 19A and 19B graphically illustrate the plunger force results ofthese tests. FIG. 19B provides the raw data points comparing F_(i)(left) to F_(m) (right). As that chart shows, the forces between F_(i)versus F_(m) were substantially similar and very low. Even the highestforce readings on both sides were under 7N and the average forces wereapproximately 5N. Moreover, the average difference between F_(i) andF_(m) was only about 0.5N. In practical terms, such a differentialbetween F_(i) and F_(m) is virtually unnoticeable to a syringe handleror a patient receiving an injection therefrom. FIG. 19A illustrates theaverage plunger force profile along a 30 mm travel distance in thesyringe barrel, again showing an average force of about 5N, whichremained very consistent between initiation and glide over the length ofthe barrel.

In terms of percentages, the average breakout force being about 5.5 Nwith the average glide force being about 5.0 N, that equates to lessthan a 10% differential between average F_(i) and F_(m).

A separate group of eight plungers and syringes having essentially thesame configuration as their counterparts described with respect to FIGS.19A and 19B, except without liquid in the syringe (i.e., dry) were alsosubjected to the same plunger force testing. This separate group ofplungers demonstrated plunger forces generally between 4.3 N to 7.5 N inempty or dry syringes, as shown in FIG. 20.

The foregoing results demonstrate that the invention can be used todeliver injectable medications to a patient without applying too muchpressure and without dramatic changes in the amount of force necessaryfrom initial actuation of the plunger through completion of delivery.Moreover, this may be achieved without flowable lubricant between theplunger and syringe wall. This is a notable achievement.

Example 2: CCI Testing Using Vacuum Decay

The previous example demonstrated the surprisingly low and consistentplunger force that plungers, according to an aspect of the invention,are capable of providing. The present example tested the “competingconsideration” of CCI (“competing’ with respect to plunger force, asdiscussed in the Background section above). CCI was tested using thevacuum decay method, as discussed above under the subsection heading,“Industry Standards for Testing Aspects of Plunger.”

Plungers subjected to this test had the configuration of the convertibleplunger 324 of FIGS. 10-12 and were assembled and set into storagesealing mode within plastic syringes having tri-layer coating sets 400(FIG. 1A) deposited on the inner surfaces thereof. The particular focuswith this test—aside from testing plunger CCI generally—was to determineany correlation between plunger shaft diameter and CCI. The plungershaft diameter refers to (see FIG. 12) diameter of the annular storageplatform 344 of the central core 332, supporting the storage ring 338 inthe engagement position.

Five sets of plungers respectively having shaft diameters of 3.25 mm,3.29 mm, 3.43 mm, 3.51 mm, 3.56 mm, 3.61 mm, 3.68 mm and 3.71 mm weretested in standard 6.48 mm syringe barrels using the vacuum decaymethod. The results demonstrated that every plunger passed except forone plunger out of four having a 3.25 mm shaft diameter. While thickershaft diameter may increase the likelihood of providing CCI, it maysimultaneously affect plunger force. Thus, a balance must be struck tomanage these competing considerations.

Example 3: High Altitude Testing of Convertible Plunger

When prefilled syringes are filled with liquid contents, a gas bubble istypically formed therein. One concern with prefilled syringes is that intheir transport, shifts in temperature and pressure (e.g. from changesin altitude) present a possible risk of undesirably displacing theplunger proximately, causing it to potentially contact unsterileportions of the syringe. For example, reduced pressure at high altitudes(e.g., when the product is in a plane or truck driving through amountain pass) may cause plunger movement and provide a pathway formicrobial ingress as the plunger returns to its original position whenthe reduced pressure is removed.

As altitude increases and pressure drops, this risk of plunger movementand resulting contamination increases. A cabin in a commercial aircraftis typically pressurized to replicate pressure at 8,000 feet altitude.Trucks driving through a mountain pass may be exposed to altitudes ashigh as 12,000 feet. Packaged products in non-pressurized holds, such asin feeder aircraft, can be exposed to altitudes as high as 16,000-19,000feet.

In this example, seal movement of the plunger was assessed using vacuumpressure. A plunger was placed into a syringe, the storage ring was setinto engagement position and then placed on the test fixture. A vacuumwas generated at the flange end of the syringe to replicate airshipment. The test reproduced conditions of 20,000 feet altitude for aperiod of 16 hours. These would be regarded as exceptionally severeconditions for transport. Surprisingly, no movement of the plunger orthe storage ring was observed under such conditions. This test providedresults that substantially exceed the ASTM Standard D6653/D6653M-13Standard Test method for Determining the Effects of High Altitude onPackage System by Vacuum Method, which requires positive results at14,000 to 16,000 feet for a period of one hour.

While the invention has been described in detail and with reference tospecific examples thereof, it will be apparent to one skilled in the artthat various changes and modifications can be made therein withoutdeparting from the spirit and scope thereof.

What is claimed is:
 1. A convertible plunger comprising: a. an internalportion and a generally cylindrical exterior surface that surrounds atleast part of the internal portion; b. the generally cylindricalexterior surface comprising a compressible and resilient storage sealingsection that is maintained in an expanded state by outward radialpressure provided by the internal portion; c. the internal portion beingcomparatively more rigid than the storage sealing section; d. theexpanded state being reducible to a constricted state by an operationthat is applied to the internal portion of the plunger to reduce oreliminate the outward radial pressure; e. the storage sealing section inthe constricted state: i. having a reduced maximum diameter orcross-sectional width than the storage sealing section in the expandedstate; and/or ii. being less resistant to inward radial compressioncompared to the storage sealing section in the expanded state; f.wherein the storage sealing section is configured to be set in theexpanded state through application of a setting force onto theconvertible plunger in a distal direction when the convertible plungeris disposed in a medical barrel; g. the operation being application ofan actuation force onto the convertible plunger in the distal directionwhen the convertible plunger is disposed in the medical barrel; h. theconvertible plunger further including a liquid sealing section on adistal end of the convertible plunger, the liquid sealing section havinga generally cylindrical exterior surface configured to provide a sealagainst an inner wall of the medical barrel when the convertible plungeris disposed therein, the liquid sealing section having a film or a capcovering a product-facing surface and a sidewall of the liquid sealingsection.
 2. A pre-filled syringe comprising: a. a medical barrel havingan inner wall and an injectable drug product disposed in a productcontaining area of the medical barrel, the medical barrel having adistal dispensing end for dispensing the injectable drug product and anopen proximal end configured for receipt of a convertible plunger; andb. a convertible plunger according to claim 1 disposed within themedical barrel.
 3. (canceled)
 4. A convertible plunger comprising: a. aninternal portion and a generally cylindrical exterior surface thatsurrounds at least part of the internal portion; b. the generallycylindrical exterior surface comprising a compressible and resilientstorage sealing section that is maintained in an expanded state byoutward radial pressure provided by the internal portion; c. theinternal portion being comparatively more rigid than the storage sealingsection; d. the expanded state being reducible to a constricted state byan operation that is applied to the internal portion of the plunger toreduce or eliminate the outward radial pressure; e. the storage sealingsection in the constricted state: i. having a reduced maximum diameteror cross-sectional width than the storage sealing section in theexpanded state; and/or ii. being less resistant to inward radialcompression compared to the storage sealing section in the expandedstate; f. a plunger head provided at a distal end of the convertibleplunger, the plunger head comprising a liquid sealing section configuredto provide a liquid tight seal and a CCI seal against an inner wall of amedical barrel, wherein the plunger head comprises a first component; g.the storage sealing section being mounted to and axially movable about asecond component or integral with the second component; h. wherein thefirst component and second component are separate components that areassembled to form the convertible plunger.
 5. A pre-filled syringecomprising: a. a medical barrel having an inner wall and an injectabledrug product disposed in a product containing area of the medicalbarrel, the medical barrel having a distal dispensing end for dispensingthe injectable drug product and an open proximal end configured forreceipt of a convertible plunger; and b. a convertible plunger accordingto claim 4 disposed within the medical barrel. 6.-9. (canceled)
 10. Thesyringe of claim 2, wherein flowable lubricant is absent from theproduct containing area.
 11. The syringe of claim 2, wherein the barrelis made from an injection moldable thermoplastic resin and has anorgano-siloxane coating or layer on the interior wall thereof. 12.-13.(canceled)
 14. The syringe of claim 2, wherein the storage sealingsection in the expanded state forms a CCI and gas-tight seal over aproduct shelf-life of 24 months.
 15. The syringe of claim 2, wherein theplunger provides a break loose force and glide force below 10 N andwherein the plunger provides a differential between break loose forceand glide force of below 1.0 N, entirely without the presence of aflowable lubricant between the barrel and the plunger'sbarrel-contacting surfaces. 16.-18. (canceled)
 19. The syringe of claim2, wherein the storage sealing section includes at least two annularribs separated by an annular valley therebetween. 20.-22. (canceled) 23.The syringe of claim 2, wherein the syringe is a component of an autoinjector. 24.-25. (canceled)
 26. The syringe of claim 2, wherein thestorage sealing section is on an outer storage ring disposed about theconvertible plunger, the convertible plunger being configured to axiallytranslate distally relative to the storage ring when transitioning fromstorage mode to dispensing mode.
 27. The syringe of claim 2, a. theinjectable drug product comprising a polypeptide composition or proteincomposition that is susceptible to one or more of the following negativeeffects from interaction with particles generated from a flowablelubricant: i. denaturing of proteins in the composition; ii.agglomeration of proteins in the composition; iii. degradation ofproteins in the composition; iv. triggering an undesired immune responsein a patient; and v. degrading efficacy of the drug product; b. whereinflowable lubricant-generated particles are absent from the drug productsuch that the drug product is not subject to the one or more of thenegative effects from flowable lubricant-generated particles. 28.-30.(canceled)
 31. A convertible plunger comprising: a. a first subassemblycomprising a connector body having a distal end and a proximal end, thefirst subassembly further comprising a plunger head, which is a separatecomponent that is assembled to the distal end of the connector body, theplunger head having a liquid sealing section configured to contact andprovide a seal against an interior wall of a medical barrel whendisposed therein; b. a second subassembly comprising an elongate ringcarrier having a distal end and a proximal end, the distal end of thering carrier being secured to the proximal end of first subassembly, theproximal end of the ring carrier configured to be secured to a plungerrod, the ring carrier comprising, from its proximal end, an annulardispensing platform and an annular storage platform distal to thedispensing platform, the annular storage platform having a largermaximum diameter or cross-sectional width than the dispensing platform,the second subassembly further comprising a compressible and resilientstorage ring disposed about the ring carrier and configured to displaceaxially thereon; c. wherein the storage platform is comparatively morerigid than the storage ring.
 32. The convertible plunger of claim 31,the proximal end of the connector body comprising a recess or axialchannel, the ring carrier further comprising an annular insertionplatform distal to the annular storage platform, the annular insertionplatform having a smaller maximum diameter or cross-sectional width thanthe storage platform, the insertion platform being disposed in therecess or axial channel so as to fixedly secure the first subassembly tothe second subassembly.
 33. The convertible plunger of claim 32,comprising a fluoropolymer film wrapped about the liquid sealingsection.
 34. The convertible plunger of claim 29, wherein the storagering includes at least two annular ribs separated by an annular valleytherebetween. 35.-94. (canceled)
 95. The convertible plunger of claim 1,wherein the film or cap comprises a fluoropolymer.
 96. The syringe ofclaim 5, wherein flowable lubricant is absent from the productcontaining area.
 97. The syringe of claim 5, wherein the barrel is madefrom an injection moldable thermoplastic resin and has anorgano-siloxane coating or layer on the interior wall thereof.
 98. Thesyringe of claim 5, wherein the storage sealing section in the expandedstate forms a CCI and gas-tight seal over a product shelf-life of 24months.
 99. The syringe of claim 5, wherein the plunger provides a breakloose force and glide force below 10 N and wherein the plunger providesa differential between break loose force and glide force of below 1.0 N,entirely without the presence of a flowable lubricant between the barreland the plunger's barrel-contacting surfaces.
 100. The syringe of claim5, wherein the storage sealing section includes at least two annularribs separated by an annular valley therebetween.
 101. The syringe claim5, wherein the syringe is a component of an auto injector.
 102. Thesyringe of claim 5, wherein the storage sealing section is on an outerstorage ring disposed about the convertible plunger, the convertibleplunger being configured to axially translate distally relative to thestorage ring when transitioning from storage mode to dispensing mode.103. The syringe of claim 5: a. the injectable drug product comprising apolypeptide composition or protein composition that is susceptible toone or more of the following negative effects from interaction withparticles generated from a flowable lubricant: i. denaturing of proteinsin the composition; ii. agglomeration of proteins in the composition;iii. degradation of proteins in the composition; iv. triggering anundesired immune response in a patient; and v. degrading efficacy of thedrug product; b. wherein flowable lubricant-generated particles areabsent from the drug product such that the drug product is not subjectto the one or more of the negative effects from flowablelubricant-generated particles.